Endothelin converting enzyme (ECE)

ABSTRACT

PCT No. PCT/EP94/03706 Sec. 371 Date May 16, 1996 Sec. 102(e) Date May 16, 1996 PCT Filed Nov. 10, 1994 PCT Pub. No. WO95/14095 PCT Pub. Date May 26, 1995The invention relates to endothelin-converting enzymes containing the polypeptide sequence described in SEQ. ID. NO. 30 or SEQ. ID. NO. 36 or functional fragments thereof, genes which code for such enzymes, and processes for producing the said enzymes and the use thereof.

This is a 371 of international application no. PCT/EP94/03706 filed on Nov. 10, 1994.

The present invention relates to endothelin converting enzymes, to processes for their preparation and to their use.

Elevated endothelin levels are thought to be associated with a large number of disorders such as essential hypertension, myocardial infarct, acute kidney failure, shock or heart failure. An association of this type is also suggested by the results obtainable with endothelin antibodies. In animal models it was possible therewith to reduce the size of a myocardial infarct dose-dependently (Watanabe et al., Nature 344, 114 (1990)), to have a beneficial effect on kidney function (Kon et al., J. Clin. Invest. 83, 1762 (1989)), and to reduce the nephrotoxicity of cyclosporin (Kon et al., Kidney Int. 37, 1487 (1990)).

Endothelin converting enzyme (ECE-1) liberates endothelin 1 from the precursor molecule big endothelin 1 which consists of 38 amino acids. The unwanted biological effects caused by endothelin 1 can be counteracted, for example, by inhibiting endothelin converting enzyme and thus endothelin 1 biosynthesis.

Enzyme activities which liberate endothelins or endothelin-like molecules from the corresponding precursor molecules, the big endothelins, have been isolated from various cell lines (Takeda et al., Biochem. Biophys. Res. Comm. 176, 860 (1991), Ohnaka et al., Biochem. Biophys. Res. Comm. 168, 1128 (1990); Matsumura et al. FEBS Lett. 293, 45 (1992), Ahn et al. Proc. Natl. Acad. Sci. U.S.A. 89, 8606 (1992), PCT WO 92/13944, Ohnaka et al. Clin. Exp. Hypertension A 14; No. 4 (1992), Okada et al. Biochem. Biophys. Res. Comm. 180, 1019 (1991), Takada et al. Biochem. Biophys. Res. Comm. 182, 1383 (1992), Opgenorth et. al. FASEB 6, 2653 (1992)).

However, these enzyme activities have not to date been adequately characterized. They are in the form of enzyme mixtures which have not been greatly concentrated. However, impure enzyme mixtures of these types are not very suitable for use in assay methods for finding specific ECE inhibitors because foreign proteases which are of no physiological relevance considerably interfere with the enzyme assay.

Thus, big endothelin is cleaved, for example, also by the serine protease chymothrypsin [sic] as well as by papain, thermolysin and NEP 24.11 to endothelin and endothelin-like products which are incorrectly assigned to the enzyme ECE in assay methods. As a consequence, there are contradictions in the description of endothelin converting enzyme in the literature.

The statements about the molecular weight of endothelin converting enzyme vary from 65 KDalton to 540 KDalton; the statements about Km and vmax values likewise differ considerably from one another (Opgenorth et al. FASEB 6, 2653 (1992); Sawamura et al. Biochem. Biophys. Acta 1161,295 (1993)). There are also contradictions about whether endothelin converting enzyme is to be assigned to the family of aspartate proteases or of metalloproteases (Sawamura et al. Biochem. Biophys. Acta 1161,295 (1993); Biochem. Pharmacol. 43,845 (1992). Furthermore, contradictory statements about characteristic information as to whether the metalloprotease is a cytoplasmic or membrane-bound enzyme, and which substrates are converted by the particular ECE (big Et-1; big Et-3), are to be found in the literature: Matsumura et al. (FEBS Lett. 293, 45 (1992)): Takahashi et al. (J. Biol. Chem. 268;21394 (1993)); Okada et al. (Biochem. Biophys. Res. Comm. 180, 1019 (1991)); Ohnaka et al. (Clin. Exp. Hypertension A 14; No. 4 (1992)); Matsumura et al. (FEBS Lett. 305;86 (1992)).

To date no unambiguous description of ECE making it possible satisfactorily to define ECE has been shown. Such a definition may be possible only through determination of the primary structure, of the amino acid sequence, of ECE. For this it is necessary first to prepare ECE in pure form.

It is an object of the present invention to prepare endothelin converting enzyme in pure form.

We have found that this object is achieved by an endothelin converting enzyme having a molecular weight of 250,000 Dalton and the partial amino acid sequence SEQ ID NO: 1.

The endothelin converting enzyme according to the invention has the following features: it has a molecular weight of about 250,000 Dalton determined by SDS polyacrylamide gel electrophoresis under non-reducing conditions.

Under reducing conditions in SDS polyacrylamide gel electrophoresis it shows a band of about 125,000 Dalton; it presumably consists of a homodimer.

Endothelin converting enzyme is glycosylated. Enzymatic removal of the sugar residues alters the apparent molecular weight from 125,000 Dalton to about 82,000 Dalton.

Sequencing of tryptic peptides of endothelin converting enzyme provides the following partial amino acid sequences SEQ ID NO: 1,2,3,4,5,6.

Further characterization of the endothelin converting enzyme according to the invention is undertaken in the examples.

The invention furthermore relates to endothelin converting enzymes which have a molecular weight of about 250,000 Dalton and a partial amino acid sequence which display [sic] at least 80% homology with SEQ ID NO: 1.

Such endothelin converting enzymes can be isolated from organisms other than cattle, for example from human cells.

The invention furthermore relates to endothelin converting enzymes which comprise the polypeptide sequence described in SEQ ID NO: 30 and SEQ ID NO: 36 or functional fragments thereof.

Functional fragments mean those partial sequences which still have the enzymatic activity of endothelin converting enzyme, the antigenic properties or the affinity for ligands, for example binding proteins.

Other functional fragments are those polypeptide sequences which are obtainable, starting from SEQ ID NO: 30 or NO: 36 by insertion, deletion or substitution of amino acids or peptides and which still have essentially the enzymatic activity of endothelin converting enzymes and/or cross-react immunologically with the endothelin converting enzymes of formula SEQ ID NO: 30 or NO: 36.

The invention furthermore relates to DNA sequences which code for an endothelin converting enzyme and which are selected from the group formed by

a) DNA sequences with the structure described in SEQ ID NO: 29 or SEQ ID NO: 35,

b) DNA sequences which code for proteins having the structure described in SEQ ID NO: 30 or SEQ ID NO: 36, and

c) DNA sequences which hybridize under standard conditions with DNA sequences a) or b),

d) DNA sequences which encode protein products which are recognized by antibodies which have been generated against the proteins of SEQ ID NO: 30 or 36 or fragments thereof.

Standard conditions mean, for example, temperatures from 42 to 58° C. in an aqueous buffer solution with a concentration of from 0.1 to 1×SSC (1×SSC: 0.15 M NaCl, 15 mM sodium citrate pH 7.2). The experimental conditions for DNA hybridization are described in textbooks of genetic engineering, for example in Sambrook et al., "Molecular Cloning", Cold Spring Harbor Laboratory, 1989.

The preparation of such DNA sequences is described in Example 8. DNA sequences whose protein products are recognized by antibodies which have been generated against the proteins of SEQ ID NO: 30 or 36 or fragments thereof can be obtained by methods which have been described well.

The raising of antibodies against such proteins is described, for example, in Hudson, L. and Hay, F. C., "Practical Immunology", Blackwell Sci. Pub., Oxford, 1980.

The use of antibodies for finding cDNA sequences which encode proteins cross-reacting with these antibodies is described, for example, in "DNA Cloning Vol. I", Glover, D. M., Ed., IRL Press Oxford, 1985.

The invention furthermore relates to processes for the preparation of endothelin converting enzymes, which comprise mammalian cells, preferably endothelial cells, being stimulated with an inhibitor of endothelin converting enzyme to overproduction of endothelin converting enzyme, and endothelin converting enzyme being isolated from these cells by conventional protein chemical procedures.

All ECE inhibitors can be used for induction of ECE in mammalian cells. ECE inhibitors suitable for this purpose are described, for example, in JP-146737; JP05148277-A1; Jpn J. Biochem. 64; (8) Abst. 2367 (1992); Derwent NCE-93-0956 (1993); Derwent NCE-93-0971 (1993); J. Med. Chem. 36,173 (1993); EP 518299-A2. Phosphoramidon is preferably used. The cells are stimulated in culture by adding these inhibitors to the cell culture medium for 6 hours to 6 days. However, the stimulation is preferably carried out for 2-3 days. The inhibitor concentrations used are from 10⁻² M to 10⁻⁷ M, preferably 10⁻³ M to 10⁻⁴ M.

The endothelin converting enzymes according to the invention can, however, also be prepared by genetic engineering means. It is possible on the basis of the described partial amino acid sequences to prepare synthetic oligonucleotides which encode these sequences or are complementary to sequences coding therefor. These oligonucleotides can be used as hybridization probe for isolating the corresponding genes or the cDNA molecules from gene pools such as gene banks or cDNA pools. This manner of gene isolation is known to the skilled worker from textbooks of molecular biology such as Sambrook, Fritsch, Maniatis; Molecular Cloning, Cold Spring Harbor Laboratory Press, 1989, U.S.A.

It is likewise possible to obtain parts of the gene, for example from cDNA banks or first strand cDNA using suitable synthetic oligonucleotides and the polymerase chain reaction (PCR) (PCR Protocols; Academic Press; San Diego; U.S.A.; 1990). Oligonucleotides suitable for this purpose can be deduced from the peptides described by Seq ID No. 1 to No. 6 by translating the amino acid sequence into the double-stranded DNA sequence (with sense and antisense). It is possible in this case, because of the degeneracy of the genetic code, for degenerate oligonucleotide mixtures to be derived from one peptide and used as primers. The oligonucleotides can also be derived from the peptides taking account of the codon usage, the preferential use in a species, in this case cattle, of particular nucleotide triplets for an amino acid. The PCR is then carried out with two different oligonucleotides as primers, in which case the two primers necessary for the PCR can be composed of the strand (sense) and complementary strand (antisense) of the oligonucleotides. It is likewise possible to use oligonucleotides which are derived from parts of the cDNA vector, or oligo-dT for the 3' part of mRNA.

These gene parts can then in turn be used in order to obtain by the process of gene isolation the complete gene or the complete cDNA.

It is possible in this way to isolate not only genes for endothelin converting enzymes which have exactly the partial amino acid sequence described in SEQ ID NO:1 but also genes for variants or endothelin converting enzymes from other organisms, for example humans, which display at least 80% homology at the protein level with SEQ ID NO: 1.

The endothelin converting enzymes according to the invention can be prepared particularly well by isolating the corresponding genes and expressing these genes in a host organism using conventional methods of genetic engineering.

The ECE according to the invention or peptides derived therefrom can be used for preparing antibodies or antibody fragments such as F_(v) fragments, which can be employed, for example, for the determination of ECE, in assay methods for identifying ECE inhibitors or as ECE inhibitors.

Such antibodies are generally valuable aids in the diagnosis of diseases in which endothelin converting enzymes are involved.

It is also possible to use for these purposes PCR primers derived from the DNA sequences according to the invention, in order, for example, to measure the ECE transcription or determine the geno-type.

The resulting genes can be used in a manner known to the skilled worker to modify the complement of genes in animals in such a way that they acquire one or more extra copies of this gene or that the normal ECE gene is switched off. These transgenic animals are suitable, inter alia, for experimental purposes.

Endothelin converting enzymes themselves are also suitable as active ingredient for producing drugs, for example for disorders in which elevated levels of ECE substrates, such as bradykinin, substance P, somatostatin, neuropeptide Y, are present. Examples of such disorders are inflammations, asthma, migraine, rheumatism, cellular processes and cell proliferation taking place with involvement of peptides as growth factors. ECE can also be used as drug for diseases in which vasodilatation which can be eliminated by administration of ECE is present, eg. septic shock, migraine, disturbances of potency.

To use ECE as drug it may be necessary in some circumstances to alter parts of the ECE by mutation. These mutational alterations may lead, for example, to an ECE derivative which is not glycosylated or which contains no membrane anchor (soluble ECE). Such a soluble ECE which no longer contains a membrane anchor can be prepared, for example, by expressing an ECE fragment which contains an extracellular, catalytically active domain. ECE fragments of this type can be obtained, for example, by linking the coding sequence from amino acid 20 to 703 from SEQ ID NO: 25, preferably from amino acid 27 to 703 from SEP [sic] ID NO: 25, to the DNA sequence of a signal peptide which can be eliminated in vivo, and introducing, in a suitable expression vector known to the skilled worker, into eukaryotic cells. An example of a suitable signal peptide is the sequence of human tissue plasminogen activator from amino acid position -35 to -4 (Collen, D., Nature 301, 214 to 221 (1983)). In this connection, alterations may influence, for example, the specificity, the duration of action or the uptake. Furthermore, functional parts of ECE can be coupled to parts of other proteins in order to generate novel proteins which are used as drugs. ECE can also be altered by covalent modification with non-peptide molecules such as PEG, dextran or fatty acids.

The DNA sequences according to the invention are also suitable for use in gene therapy, for example for producing medicines for gene therapy. Diseases with elevated endothelin levels can also be treated with oligonucleotides derived from the ECE DNA sequence. These oligonucleotides are derived from the non-coding DNA strand (antisense) and can be used as drugs. An antisense therapy based on this preferably makes use of more stable chemical derivatives derived from the oligonucleotides. For example, it is possible to use antisense oligonucleotides which are preferably synthesized from the region defined by positions 31 to 100 Seq ID [sic]: 35. The antisense oligonucleotides preferably have a length of from 15 to 30 residues. Antisense therapy or prevention of diseases is used for the same indications as ECE inhibitors, eg. cerebral ischemias; subarrachnoid [sic] hemorrhages; vasospasms; coronary ischemias; disorders associated with cell proliferation processes, such as prostate hyperplasia, such as atherosclerosis, such as restenosis; asthma; hypertension; pulmonary hypertension; organ failure such as heart failure and kidney failure; renal ischemias; neprotoxicity [sic]; myocardial infarct; coronary heart disease; sepsis.

It is also possible to derive from the DNA sequence of ECE sequences with which catalytic RNA molecules can be generated, which are called ribozymes. These catalytic RNA molecules act by cleaving or inactivating, after administration, the ECE RNA or ECE DNA and thus preventing synthesis of ECE protein.

The ECE DNA sequences can be used with suitable expression vectors in order to establish cells which express this enzyme. These cells are used inter alia as drugs.

The endothelin converting enzymes are preferably used in assay methods for identifying ECE inhibitors. These assay methods are, as a rule, enzymatic reactions in which the ECE-catalyzed cleavage of a substrate is measured in the presence of potential inhibitors.

The invention furthermore relates to inhibitors for endothelin converting enzymes which are identified with an enzyme assay using the endothelin converting enzymes according to the invention.

The invention also includes a process for producing drugs which inhibit an endothelin converting enzyme, which comprises employing known chemical compounds in an enzyme assay using the endothelin converting enzymes according to the invention and identifying those with an inhibiting effect, and formulating compounds identified in this way with conventional vehicles and ancillary substances as drugs.

EXAMPLE 1

Stimulation of ECE-1 in FBHE Primary Bovine Endothelial Cells by Phosphoramidon

Three tubes with frozen FBHE bovine endothelial cells (ATCC CRL 1395) were thawed in the 14th passage and introduced into 3 T175 cell culture bottles (from Sarstedt) each containing 40 ml of DMEM growth medium (Gibco No. 041-01965).

+5 ml/500 ml glutamine (200 mM; Gibco 043-05030)

+1 ml/500 ml gentamicin (Gibco 043-05750)

+non-essential amino acids; final concentration: 1×(Gibco No. 043-01140)

+10% FCS (Gibco No. 011-06290; inactivated for 37 minutes at 56° C.)+25 ng/ml basic FGF (Intergen 4125-80)).

These cells were incubated by standard methods at 37° C. in an atmosphere of 7% CO₂, 100% humidity. The medium was changed the next day. When confluence was reached, in this case after 4 days, the cells were passaged in accordance with standard methods by trypsin treatment, and distributed into 9 T-175 bottles and incubated at 37° C. for growth as described. After confluence was reached after 3 days, the cells were again distributed to 20 T bottles in accordance with standard methods by trypsin treatment. After a further 3 days it was possible to distribute the cells to 40 T bottles. After a further 3 days, 39 of these T bottles were distributed to 78 T bottles. Since these 78 T bottles are used to harvest the cells, suitable cell culture bottles (from Costar; Accell; No. 3155) are used for this purpose. On the day after inoculation of these T bottles, phosphoramidon (from Peptide Institute; No. 4082; abbreviated to PHAM) was added in a final concentration of 10⁻⁴ M to 68 bottles (+PHAM). This treatment leads to induction of ECE activity. The remaining 10 T bottles were included as non-induced control cells (-PHAM). After incubation under the described conditions for a further 2 days, the PHAM-induced cells and the control cells (-PHAM) were harvested separately. This was done by opening the bottles and tipping out the medium. The cells were washed in the T bottle with 10 ml of PBS (Boehringer Mannheim No. 210331) in each case (ie. cautiously swirled over the cell lawn). The PBS was tipped out. 5 ml of PBS were again added to each T bottle. The cells were scraped off the bottom of the culture bottle using a cell scraper (from Costar No. 3010) and transferred as cell suspension into a 150 ml centrifuge tube (Falcon No. 2076), where they were stored on ice. Each T bottle was then rinsed with 10 ml of PBS. The cell suspension from the rinsing was combined with the cell suspension present in the centrifuge tubes. The cells were sedimented by centrifugation (1200 rpm; 10 minutes; Heraeus Christ Minifuge GL No. 4400; Rotor 2150). The cell-free supernatant was discarded, and the pellet was taken up in PBS in 3 times the volume of the cell sediment. After centrifugation again, the cell-free supernatant was again discarded. The pellet remained on ice until worked up.

EXAMPLE 2

Comparative enrichment of non-stimulated and phosphoramides-stimulated [sic] FBHE bovine endothelial cells; identification of the protein.

The FBHE cells obtained in Example 1 with and without phosphoramidon induction (in each case 500 μl of moist mass) were treated with ultrasound in 15 ml of PBS buffer, 0.5 mM diisopropyl fluorophosphate in an icebath for 20 minutes. After centrifugation (1000 g, 20 min), the membranes were precipitated by adding 5% Pluriol F68® to the supernatant and were obtained by centrifuging again at 10,000 g. The membranes were digested with 2 ml of 100 mM Tris buffer, pH 8.0, and solubilized with 1% Triton X-100®. The solubilisates (2.5 ml each) were centrifuged, and the residues were discarded.

Mono-Q® Chromatography

The solubilisates of the ±phosphoramidon-induced cells were chromatographed separately on a Mono Q® HR 5/5 column (from Pharmacia) under exactly identical conditions. The column is equilibrated with 50 ml of Tris buffer, pH 8.0, 0.1% Triton X-100 (A buffer). The solubilisate is loaded on and then washed with A buffer for 15 min, and a linear gradient with B buffer (A buffer+1 M NaCl is run for 50 min (flow rate 0.2 ml/min). 20 fractions of 0.5 ml are collected and assayed with human big Et-1 as substrate. The Et-1 which is produced is detected and quantified by reversed phase HPLC in the manner described (Example 3). The two fractions with the highest enzyme activity are combined in each case.

Superose 12® Gel Chromatography

The eluates from the Mono Q chromatographies are concentrated to 250 μl using Centricon® tubes (from Amicon) and, in each case, subjected to gel chromatography on Superose 12 HR10/36.

    ______________________________________                                         Conditions: Buffer:    20 mM sodium phosphate,                                                           250 mM NaCl, pH 7.4,                                     0.05% Triton × 100                                                      Flow rate: 0.5 ml/min                                                          Fraction: 0.5 ml                                                            ______________________________________                                    

The fractions are assayed by the assay described in Example 3, and in each case the two fractions with the highest enzyme activity are combined.

Protein was determined in all fractions by the method of Bradford (Anal. Biochem. 72, 248 (1976)).

Results

The purification of stimulated and unstimulated cells gave the following results at the various purification stages:

    ______________________________________                                                        Spec. act. [μU/mg]                                                                       μg/mg                                             Purification FBHE cells FBHE cells                                             step + phosphoramidon - phosphoramidon                                       ______________________________________                                         Membranes      129          44                                                   Solubilisate 188 22                                                            Mono Q chromat. 1470  78                                                       Superose 12 chromat. 4500  130                                               ______________________________________                                    

The two active fractions from the Superose 12® chromatography were loaded onto an 8% SDS polyacrylamide gel for comparison. The gel pattern of purified ECE-1 from phosphoramidon-treated cells shows an additional band at 250,000 Dalton when compared with untreated cells. When the proteins are loaded on with the reducing agent dithiothreitol (DTT), comparison shows an additional band at 125,000 Dalton.

EXAMPLE 3

ECE-1 Activity Assay by HPLC

Conversion of big endothelin-1 into endothelin-1 by endothelin converting enzyme (ECE-1)

1 μl of enzyme solution obtained as in Example 4 was mixed with 21 μl of 50 mM Tris, 50 mM imidazole, 250 mM NaCl, pH 7.4 buffer and 2.5 μl of human big endothelin (2 mg/ml in 0.1% acetic acid in water). After 2 hours, the reaction was stopped with 72 μl of 0.5% trifluoroacetic acid in order to analyze the endothelin produced. The sample was centrifuged and the supernatant was identified and, by comparison with an endothelin standard, quantified by reversed phase high pressure liquid chromatography (RP-HPLC) analysis with UV detection (205 nm) as described in (J. Takada et al., Biochem. Biophys. Res. Comm. 176, 860 (1991), K. Ohnaka et al., Biochem. Biophys. Res. Comm. 168, 1128 (1990)).

The enzyme activity can then be calculated in activity ##EQU1##

This method was used to determine the ECE activity at various stages in the purification from the workup of FBHE cells. At the same time, the amounts of protein were determined by the method of Bradford (Anal. Biochem. 72, 248 (1976)).

EXAMPLE 4

Purification of ECE-1 from FBHE Bovine Endothelial Cells

a) Obtaining membranes, trypsinization of foreign protein

6 ml of FBHE cell pellet (from Example 1) are digested in 25 ml of PBS buffer and disrupted in an ultrasound bath while cooling in ice for 15 minutes. The cell detritus was removed by centrifugation at 10,000 g for 20 min. 3.6 mg of trypsin were added to the supernatant while stirring, and the mixture was stirred at room temperature for 1.5 h. The sample was centrifuged at 100,000 g for 1 h, and the membranes present in the residue were suspended with 25 ml of 100 mM Tris buffer, pH 8.0.

b) Solubilization of ECE-1

The 25 ml of membrane suspension was adjusted to 0.5 mM diisopropyl fluorophosphate and then 0.5% Triton X-100® and stored in an icebath overnight.

c) Mono-Q® chromatography

A Mono-Q® FPLC column, HR16/10, from Pharmacia was equilibrated with 50 mM Tris buffer, pH 8.0; 0.05% Triton X 100® (A buffer).

The solubilisate was loaded on and then washed with A buffer for 30 min, and elution was subsequently carried out with a linear gradient to buffer B (buffer A+1 m NaCl) over the course of 100 minutes. 30 fractions of 10 ml each are collected. The protein content of the samples is determined by the Bradford method, and the ECE-1 activity is determined as in Example 3.

The two fractions with the highest specific activity were combined.

d) Gel filtration

The combined Mono-Q® eluates from 4c) were concentrated to 500 μl through a 30 KDa Centricon membrane (from Amicon).

A Superose 12® HR 10/30 column (from Pharmacia) is equilibrated with 20 mM Na phosphate buffer, pH 7.4, 250 mM NaCl, 0.05% Triton X-100, and the concentrated sample is loaded on. Chromatography is carried out with the equilibration buffer at a flow rate of 0.5 ml [sic], and 0.5 ml fractions are collected.

The specific activity of the fractions is determined as in 4c). The fraction with the highest specific activity is indicated under e); it elutes at about 250,000 Dalton, using standard proteins for calibration under identical chromatography conditions.

e) Results

    ______________________________________                                                             Spec. activity                                             Purification step                                                                              Protein [mg]                                                                             [μU/mg]                                           ______________________________________                                         Membranes       87         410                                                   Solubilisate 87  360                                                           Mono Q eluate 6.6  3760                                                        Superose 12 eluate 0.35 15100                                                ______________________________________                                    

EXAMPLE 5

SDS Gel Analysis of Purified ECE-1 from FBHE Cells

The ECE-1 purified in Example 4 is analyzed on an 8% SDS gel by the method of Lammli (Nature 227, 680 (1979)) under non-reducing and reducing conditions (+DTT). This shows that ECE-1 has a molecular weight of 250,000 Dalton in the non-reduced state and, after reduction, disintegrates into a broad band around 125,000 Dalton.

EXAMPLE 6

Deglycosylation of ECE-1

50 μl of the ECE-1 solution purified in Example 4 were adjusted to an SDS content of 0.25% with 10% strength SDS solution. The samples were incubated at room temperature for 20 min and adjusted to 1% Triton X-100. After 20 min at RT, 5 μl of 250 mM Na phosphate buffer, pH 4.7, were added. Then 0.25 μl of PNGase and 0.5 μg of Endo F were added. The samples were incubated at 37° C. for 8 h. The same amounts of enzymes were then again added and incubation was continued at 37° C. for 8 hours. The samples were then concentrated to 50 μl and analyzed in a 4-12% SDS gel.

Results

In the reduced state, the apparent molecular weight of 125,000 Dalton is altered by elimination of the sugar residues with the PNGase F/Endo F mixture to about 82,000 Dalton.

EXAMPLE 7

Partial Sequences of the ECE-1 from Bovine Endothelial Cells

16×25 μg of the ECE-1 solution obtained in Example 4 were loaded onto preparative 4-12% SDS polyacrylamide gradient gels. After conventional staining with Coomassie blue, the gel is destained and hydrated in pure water for 4×40 minutes. The stained bands at 250 KDa were cut out with a scalpel and digested with 200 μl of 100 mM NH₄ HCO₃ solution. 0.5 μg of trypsin is added and the mixture is incubated overnight, and the supernatant is then removed. The residue is again incubated with 0.5 μg of trypsin in 200 μl of 100 mM NH₄ HCO₃ buffer at room temperature for 5 h. The sample is then concentrated to dryness in a speed-vac concentrator. The residue is taken up in 40 μl of water and stirred with 4 μl of 40 mM dithiothreitol solution for 30 min. Then, at 37° C., 4 μl of 100 mM iodoacetamide solution were added. After 2 hours, the sample is concentrated to dryness.

The resulting peptides were fractionated on a 1 mm×15 cm reversed phase HPLC column in a linear gradient from 0.5% trifluoroacetic acid in water to 0.5% trifluoroacetic acid in 90% acetonitrile in 3 hours. UV-active fractions were collected, and the primary sequences were determined in a gas phase sequencer.

Results

The following partial sequences were determined: SEQ ID NO: 1: - Xaa-Xaa-Pro-Asn-Ala-Leu-Asn-Phe-Gly-Gly-Ile-Gly-Val- Val-Val-Gly-His-Glu-Leu-Thr-His-Ala-Phe . . . - SEQ ID NO: 2: - Xaa-Tyr-Xaa-Lys-Xaa-Gly-Asn-Leu-Arg-Pro - SEQ ID NO: 3: - Xaa-Ile-Ala-Xaa-Glu-Thr-Glu-Leu-Glu-Ile . . . (Ile)(Ile) - SEQ ID NO: 4: - Xaa-Pro-Glu-Phe-Leu-Leu-Glu-Gly-Leu-Ile-Thr-Asp-Pro . . . - SEQ ID NO: 5: - Xaa-(Gln)-(Ala)-(Glu)-Asn-Val-Ile-Gln-Val-Xaa-Gln . . . - SEQ ID NO: 6: - Val-Glu-Ile-Val-Phe-Pro-Ala-Gly-Ile-Leu-Gln-Ala-Pro-(Phe)-Tyr-Thr (Thr)

The amino acids indicated in parentheses were not identified with absolute certainty.

SEQ ID NO: 1 proves that ECE-1 is a novel protein from the metalloprotease family because, on comparison with sequences of the metalloendopeptidases NEP 24.11 and thermolysin, it shows significant homologies of 72% and 40% respectively.

EXAMPLE 8

Preparation of a cDNA Sequence Coding for an Endothelin Converting Enzyme

a) Isolation of RNA and preparation of a cDNA bank

Complete RNA from FBHE cells which have been stimulated with phosphoramidon as in Example 1, or from HeLa cells which have been stimulated with phosphoramidon as in Example 1, was obtained by disruption in guanidinium thiocyanate. This was done using the materials in accordance with the instructions in the RNA isolation kit supplied by Stratagene, La Jolla, Calif., U.S.A. (Catalog No. 200345).

The polyadenylated messenger RNA was selected from the abovementioned complete RNA from FBHE cells by oligo(dT) affinity separation. This method was carried out with materials and in accordance with the instructions of the PolyATtract mRNA Isolation System supplied by Promega, Madison, Wis., U.S.A. (Catalog No. Z5200). cDNA was synthesized from polyadenylated messenger RNA using materials and in accordance with the instructions of the ZAP-cDNA synthesis kit supplied by Stratagene, La Jolla, Calif., U.S.A. (Catalog No. 200400) and was then packaged in lambda phages using materials and in accordance with the instructions of the Uni-ZAP XR GigapackII cloning kit supplied by Stratagene, La Jolla, Calif., U.S.A. (Catalog No. 237611).

b) Preparation of oligonucleotide probes for the RACE PCR

The peptides indicated in Example 7 with SEQ ID NO:1 and NO:6 were the starting point for the cloning of cDNA fragments by the polymerase chain reaction (PCR, see Molecular Cloning, 2nd Edition (1989), Sambrook, J. et al., CSH Press, page 14.1 et seq.).

On the basis of the genetic code it is possible to deduce from SEQ ID NO: 1, position 16 to 22, an oligonucleotide mixture with nucleic acid sequence SEQ ID NO:7:

5'-GGSCAYGARYTNACNCAYGC-3'.

It is likewise possible to deduce from SEQ ID NO: 6, position 2 to 8, an oligonucleotide mixture with SEQ ID NO: 8:

5'-GARATYGTSTTYCCYGCYGG-3',

and from SEQ ID NO: 6, position 9 to 16 an oligonucleotide mixture with SEQ ID NO: 9:

5'-ATYCTSCAGGCYCCYTTYTAYAC-3'.

In this case, SEQ ID NO: 7 to NO: 9 correspond to the sequence of the coding DNA strand. Several nucleotides have been inserted at some positions because of the known degeneracy of the genetic code. This results in an up to 512-fold complexity of the mixture for SEQ ID NO: 7 to 9. Said sequences were synthesized as oligonucleotides.

The following oligonucleotides were additionally synthesized as 3' primers in the RACE PCR:

A-B-T18 (SEQ ID NO: 10):

5'-CGAGGGGGATGGTCGACGGAAGCGACCTTTTTTTTTTTTTTTTTT-3'; and

A (from A-B-T18) (SEQ ID NO: 11):

5'-CGAGGGGGATGGTCGACGG-3'; and

B (from A-B-T18) (SEQ ID NO: 12):

5'-GATGGTCGACGGAAGCGACC-3'.

The syntheses were carried out using an Applied Biosystems Type 360A DNA synthesizer. The oligonucleotides were, after removal of the protective groups, purified by gel electrophoresis on an acrylamide/urea gel.

c) Preparation of DNA templates for the PCR

5 μg of complete RNA or 1 μg of poly(A)+RNA of the RNA preparation mentioned under a) from phosphoramidon-stimulated FBHE cells were translated into single stranded cDNA (sscDNA) with 1 μg of the oligonucleotide A-B-T18 (SEQ ID NO: 10) and using the reverse transcriptase enzyme. This was done using materials and in accordance with the instructions of the Superscript Preamplification System supplied by Gibco BRL, Eggenstein, Germany (Catalog No. 8089SA). After the reaction was complete, the synthesized products were purified using the Geneclean II kit supplied by BIO 101, La Jolla, Calif., U.S.A., to remove smaller molecules and excess oligonucleotides.

d) PCRs and cloning of a part cDNA sequence

The polymerase chain reaction was carried out by known protocols (see Molecular Cloning, 2nd Edition (1989), Sambrook, J. et al., CSH Press, Page 14.1 et seq.). A DNA Thermal Cycler supplied by Perkin Elmer was used for this. Also used were the principle of "internal primers" of Frohmann, M. A. et al. (Proc. Natl. Acad. Sci. U.S.A. (1988) 85, 8998-9002) and a modification of the method of Fritz, J. D. et al. (Nucl. Acids Res. (1991) 19, 3747).

Specifically, the sscDNA from c) was amplified with, in each case, 20 pmol of the oligonucleotides SEQ ID NO: 8 and A (from A-B-T18). The conditions for this were: 1' 95° C.; 2' 55° C.; 3' 72° C. for 35 cycles.

The PCR products were fractionated by electrophoresis on a 1.2% LMP agarose/TBE gel.

About 10 gel disks were cut out of the gel over the entire length of the "tail", and these were melted as separate fractions with DNA fragments of increasing molecular weight.

Aliquots of these fractions were then employed separately in a second PCR with, in each case, 20 pmol of the oligonucleotides SEQ ID NO: 9 and B (from A-B-T18). During this the agarose content never exceeded 1/10 of the volume of the PCR mixture. Reaction conditions: 1' 95° C.; 2' 50° C.; 3' 72° C. for 35 cycles.

Fractionation by gel electrophoresis of the amplification products of these fractions clearly revealed a reduction in the complex product spectrum of the first PCR to a defined band with a length of about 1000 bp after the second PCR.

This PCR product selected in this way was eluted by standard methods. The identity of the band 1000 bp in size as a fragment of bovine endothelin converting enzyme cDNA was first checked by another, third PCR amplification using the oligonucleotides SEQ ID NO: 7 and B (from A-B-T18). The product of this PCR was a band about 950 bp in size.

After subcloning of the band 1000 bp in size from the second PCR reaction into the vector pCR II (TA Cloning Kit, Invitrogen Corp., San Diego Cat. No. K2000-01) and replication of the plasmid in E. coli DH5alpha, sequence analysis of a clone revealed an open reading frame of 189 amino acids SEQ ID NO: 13, NO: 14). The sequences for the peptide SEQ ID NO: 1, NO: 2 and NO:4 were also located in the same reading frame, which unambiguously defines the identity of the cDNA fragment.

e) Cloning of a bovine cDNA for endothelin converting enzyme

The protocol detailed in Example 1a) [sic] was used to generate a cDNA library with a random primer mixture at the step of synthesis of the first strand. The primers were synthesized as the sequence:

5'-GAGAGAGAGTCGACGGTACCN7; SEQ ID NO: 15.

As a deviation from the abovementioned cDNA synthesis protocol, the double-stranded cDNA was fractionated on a 2 ml Sephacryl S-1000 (grade: superfine; Pharmacia, Freiburg; Catalog No. 17-0476-01) column. The fractions with cDNA fragments at least 1 kb in size were concentrated by alcohol precipitation in a conventional way and subsequently treated in accordance with the instructions in the cDNA synthesis kit, with the cDNA preparation subsequently being cleaved with the restriction endonuclease SalI in place of XhoI and being integrated into the lambda vector.

2×106 [sic] clones from the bank were hybridized, after transfer to nylon membranes, with a DNA probe which was produced using the oligonucleotides

5'-CGGCCCTGGTGGAAGAACTCG-3' (SEQ ID NO: 16) and

5'-TGCGGACGGAACACCAGACCT-3' (SEQ ID NO: 17)

from the partial bovine cDNA (SEQ ID NO:13), position 136 to 156, and 391 to 412 respectively. The DNA probe was labeled in a polymerase chain reaction (PCR) in the presence of digoxigenin-dUTP as described in Example 1f) [sic]. The hybridization was carried out under stringent conditions (see Example 1f) [sic]), the last washing step being carried out after hybridization in 0.1×SSC, 60° C., and subsequently the bound DNA probe being detected immunologically. Sequencing of selected clones revealed the bovine cDNA sequence C60, SEQ ID NO: 18, with a continuous reading frame, SEQ ID NO: 19.

Then 2×106 [sic] clones from the bank were hybridized with a DNA probe which was generated using the oligonucleotides

5'-GCCAGCGCCGTCTCAAAGTCCAG-3' (SEQ ID NO: 20) and

5'-TGGGGGACCTTCAGCAACCTCT-3' (SEQ ID NO: 21)

from the cDNA clone C60, SEQ ID NO: 18, position 500 to 522, and 14 to 35 respectively, as described above, under identical conditions. Sequencing of selected clones revealed the bovine cDNA sequence SEQ ID NO: 22 with a continuous reading frame of 708 amino acids (SEQ ID NO: 23).

5×108 [sic] plaque-forming units of a commercial bovine lung cDNA bank in lambda gt11 (Clontech Laboratories, Inc.; 4030 Fabian Way; Palo Alto Calif. 94303-4607, U.S.A.; Catalog No. BL1006b) were concentrated by precipitation with 10% polyethylene glycol 6000, 1 M NaCl resuspended in 100 μl of double-distilled water and heated at 70° C. for 5 min. 5 μl of this lysate were used in a 50 μl standard PCR reaction (Example 8d) with the primers gt11 fwd and 5'-GGTGCTTGATGATGGCTTGGTTGT-3' (SEQ ID NO: 26). The primer gt11 fwd corresponds to position 2979-3003 of the β-galactosidase gene (gene bank: ECLACZ) and is located in the lambda gt11 cloning vector directly in front of the unique EcoRI integration site which was used for constructing the bank (Young, R. A. &. Davis, R. W. (1985) Genetic Engineering, Ed. by Setlow, J. U. Hollander, A. Plenum Press, New York 29-41). The primer SEQ ID NO: 26 corresponds to position 280-303 of SEQ ID NO: 22.

The amplifications were carried out over 40 cycles. The PCR product was fractionated on a 3% low melting point Nu-Sieve GTG agarose gel (supplied by FMC BioProducts, 191 Thomaston Street, Rockland, Me. 04841, U.S.A.; Catalog No. 50082), and the size range of 400-600 base pairs was fractionated by cutting out individual gel segments. The gel disks were melted as described in Example 8d), and 1.5 μl were used in 50 μl of a fresh PCR reaction with the primers gt11 fwd and 5'-AGATGGAGCTGGTCACCGAGATGC-3' (SEQ ID NO: 27). The primer SEQ ID NO: 27 corresponds to position 127-150 of SEQ ID NO: 22.

The resulting PCR fragments were sequenced after subcloning in the plasmid vector pUC18 (Yanisch-Perron, D., Vieira J. & Messing, J. (1985) Gene 33, 103-119) (SEQ ID NO: 28).

This sequence overlaps, with nucleotides 175-324, positions 1-150 in SEQ ID NO: 22 and extends it by 174 nucleotides in the 5' direction. The resulting complete sequence (SEQ ID NO: 29) encodes an open reading frame of 754 amino acids (SEQ ID NO: 30).

f) Cloning of a human cDNA for endothelin converting enzyme

Since endothelin-1 has been detected in human placenta, it was assumed that endothelin converting enzyme is also expressed in placenta. Hence a labeled bovine cDNA probe was used to screen a human λgt-11 placental cDNA bank. To prepare the bovine cDNA probe labeled with digoxigenin-dUTP, 1 ng (1 ng/ml) of the partial bovine cDNA sequence (SEQ ID NO: 13) was used as template in a PCR reaction (see Molecular Cloning, 2nd Edition (1989), Sambrook, J. et al., CSH Press, page 14.1 et seq.). The sense oligonucleotide (SEQ ID NO: 16) comprised the nucleotides from position 136 to 156 in SEQ ID NO: 13, while the antisense oligonucleotide SEQ ID NO: 17) comprised positions 392 to 412 in SEQ ID NO: 13. The following cycles were carried out 35 times in the DNA Thermal Cycler (Perkin Elmer): 2 min at 94° C., 2 min at 60° C. and 3 min at 72° C. The labeled 276 bp bovine cDNA probe was subsequently purified on an agarose gel and denatured by boiling. This probe was used to screen, under low stringency conditions, about 650,000 clones of a human placental λgt-11 cDNA bank (Clontech, HL 1008b). Hybridization of the filter extracts with the probe took place in 5×SSC, 2% blocking reagent (Boehringer Mannheim; No. 1096176), 0.1% N-laurylsarcosine, 0.02% SDS at 60° C. overnight. The filters were then washed 2×5 min at 60° C. with 2×SSC, 0.1% SDS and subsequently for 20 min at 60° C. with 0.5×SSC, 0.1% SDS. Further development of the filters for identification of the bound DIG probes took place in accordance with the Boehringer Mannheim protocol (DIG nucleic acid dedection [sic] kit No. 1175041).

Clones with the cDNA sequence indicated in SEQ ID NO: 24 were isolated. The nucleotides in position 1 to position 2109 of the cDNA sequence with SEQ ID NO: 24 code for the amino acid sequence indicated in SEQ ID NO: 25. The amino acid sequence corresponds to the major part of the primary sequence of endothelin converting enzyme because the peptides SEQ ID NO: 1 to SEQ ID NO: 6 from the trypsin peptide sequencing of the isolated endothelin converting enzyme are found in the sequence. It is also possible to identify the metalloprotease concensus sequence HEXXH as HELTH in positions 540 to 544 in amino acid sequence SEQ ID NO: 25.

A cDNA library was generated from 3 μg of placental poly A(+) RNA as described in Example 8e) using the oligonucleotide 5'-GAGAGAGAGAGAGAGAGAGAACTAGTCTCGAGCCAAGCAGGCCACCAGTCCTG-3 (SEQ ID NO: 31) as first strand cDNA synthesis primer. Nucleotides 32 to 53 correspond to positions 32 to 53 in SEQ ID NO: 24. The cDNA preparation was integrated as described in Example 8a) into the lambda vector Uni-ZAP XR. The resulting 4×105 [sic] independent clones were amplified, and 5×108 [sic] plaque-forming units were used in a 100 μl PCR reaction as described in Example 8e). The primers SEQ ID NO: 31 and C were used for this. Primer C is located in the lambda vector in the Bluescript SK(-) part, Pos. 881-904, sequence file gene bank: ARBLSKM.

The PCR reaction was carried out for 40 cycles at a hybridization temperature of 65° C. 1 μl of the reaction product was added to a fresh 50 μl PCR reaction mixture, which underwent 40 cycles at a hybridization temperature of 60° C. The primers used were oligonucleotides D and

5'-CCTGCCGCCAGAAGTACCACCAACA-3' (SEQ ID NO: 32).

Primer D is located in the Bluescript SK(-) part of the lambda Uni-ZAP XR vector (Pos. 857-880, sequence file gene bank: ARBLSKM), and the primer SEQ ID NO: 32 corresponds to position 11-35 in SEQ ID NO: 24. The reaction product was subcloned in the plasmid vector pUC18 as described above. Selected clones were sequenced.

The sequence obtained was a novel 5' portion of the human ECE cDNA (SEQ ID NO: 33, whose 3' terminal region (Pos. 188-222) lock-forms with position 1-35 in SEQ ID NO: 24. It extends it by 187 nucleotides in the 5' direction and provides the complete human ECE sequence SEQ ID NO: 35 which encodes an open reading frame of 753 amino acids (SEQ ID NO: 36).

EXAMPLE 9

Preparation of Recombinant ECE in Mammalian Cells

1. Construction of an expression vector of membrane-bound human ECE

For expression of the complete human ECE, the cDNA sequence (SEQ ID NO: 35) from nucleotide 29 to 2720 was inserted with suitable adaptors into the expression vector pcDNA3neo supplied by Invitrogen (3985 B Sorrento Valley Blvd., San Diego, Calif. 92121, U.S.A.; product No. V790-20) between the Kpn I and Xba I restriction sites. The ECE sequence provides its own translation start and stop sequences and a consensus Kozak sequence (Kozak, M. (1989) J. Cell Biol. 108, 229-241). In this vector, transcription of the ECE messenger RNA is under the control of the strong cytomegalovirus promoter. Selection of transfected cells is carried out via the neomycin resistance gene which is located in the plasmid and permits only G418-resistant colonies to grow.

2. Construction of an expression system for secreted human ECE

a) The cloning was carried out in a commercially obtainable eukaryotic expression vector pcDNA3neo supplied by Invitrogen (3985 B Sorrento Valley Blvd., San Diego, Calif. 92121, U.S.A.; product No. V790-20). For this, the vector was initially cleaved with the restriction enzymes Eco RI and Eco RV.

b) Then the nucleic acid fragment position 241-position 2396 from the cDNA of human ECE (SEQ ID NO: 35) was obtained by a polymerase chain reaction with suitable oligonucleotide primers. Owing to the choice of the sequence of the 5' primer, the nucleic acid sequence between position 241 and position 245 (SEQ ID NO: 35) was altered in the base sequence 5'-ACGCG-3'. By inclusion of position 246, this step generated a recognition sequence for the restriction endonuclease Mlu I. The resulting ECE fragment was cleaved with Mlu I in a further step.

c) As further fragment, the coding sequence of human tissue plasminogen activator (t-PA) between nucleotide 74 and nucleotide 176 of the published sequence (D. Collen, Nature 301, 214-221 (1983)) was prepared from two synthetic oligonucleotides (strand/complementary strand). In addition to the stated sequence, the synthetic oligonucleotides were provided with adapters which lead to a 5' Eco RI and 3' Mlu I protrusion.

Ligation of the fragments generated in b) and c) via the common Mlu I restriction cleavage site leads to fusion of the reading frames of the signal peptide of the human t-PA gene and of the extracellular domain of the human ECE gene. Ligation of this fusion product into the pcDNA3 vector from a), which had been cut with Eco RI and Eco RV, leads to an expression system for secreted human ECE.

Expression in mammalian cells

The DNA of the expression vectors was transfected into mammalian cells using Lipofectamine (Gibco; Life Technologies GmbH; Dieselstraβe 5, 76334 Eggenstein, Germany; No. 530-8324SA). The cells used were CHO-K1 (ATCC CCL 61); BHK-21 (ATCC CCL 10); 293 (ATCC CRL 1573) and C127I (ATCC CRL 1616).

2×10⁵ cells in each case were introduced into 3 ml of growth medium in each well of a 6-well culture plate. The transfection was carried out the next day. To do this, the cells were washed once with PBS. The transfection with Lipofectamine was carried out in accordance with the information provided by the manufacturer Gibco (Focus (1993), 15 No. 3, 73-78). Each well received 1 μg of DNA and 6 μl of Lipofectamine, which were together applied in 1000 μl of serum-free cell culture medium. After incubation at 37° C. for 6 hours, the cells were washed once with PBS and incubated with normal growth medium overnight. The next day, the cells in a well were detached using trypsin and then distributed to 1, 5 or 10 Petri dishes (10 cm diameter). The following day the transfected cells were selected by treatment with G418 (Gibco; Cat. No. 066-01811Y; tradename: Geneticin), ie. the growth medium was replaced by a medium containing 1.2 mg/ml G418. After 7-10 days, colonies of G418-resistant cells were to be seen in the Petri dishes. These were isolated by the cloning cylinder method (DNA Cloning Vol. II; Ed. D. M. Glover, IRL Press, 1985; page 220). The isolated colonies were each placed in one well of a 24-well dish with about 1.5 ml of growth medium (including G418). When confluence was reached, the cells were transferred by trypsinization into larger culture vessels.

a) Membrane-bound ECE

Cells which expressed membrane-bound ECE were investigated for the presence of ECE after cell disruption and fractionation as described in Example 1 and 2. (No phosphoramidon stimulation was carried out.) The specific activity of the analyzed colonies was up to 1550 μU/mg of protein based on membranes. Membranes of colony 38 were worked up further. The result of this was as follows:

    ______________________________________                                                        Spec. activity                                                  Purification step                                                                               (μU/mg protein)                                            ______________________________________                                         Membranes         1550                                                           Solubilisate  2010                                                             Mono-Q chromatography 12000                                                  ______________________________________                                    

b) Secreted ECE

Cells which express the ECE without membrane anchor and secrete it into the cell culture medium were assayed for the presence of the recombinant ECE by investigating the cell culture supernatant from confluent cells for ECE activity. For this purpose, the cell culture supernatant was removed after a cultivation time of 2 days, and cell detritus was removed by centrifugation at 1000 g. 6 ml of the supernatant were then concentrated using a Centricon 10,000 (Amicon, W. R. Grace+Co., Danver, Mass. 01923, U.S.A.; product No. 4206) and centrifugation at 3220 g (about 30 min). The liquid containing the low molecular weight substances which had flowed through was kept (Centricon eluate). The Centricon was washed once with 1 ml of PBS+10 mM Tris+150 mM NaCl; pH 7.5. The concentrate was taken up in 300 μl of the Centricon eluate.

18 μl of the concentrate were used in the ECE assay as described in Example 3.

The volume-based activity of the secreted ECE was up to 10 μunits/ml of cell culture medium, depending on the colony of recombinant cells investigated.

    __________________________________________________________________________     #             SEQUENCE LISTING                                                    - -  - - (1) GENERAL INFORMATION:                                              - -    (iii) NUMBER OF SEQUENCES: 36                                           - -  - - (2) INFORMATION FOR SEQ ID NO: 1:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 23 amino - #acids                                                  (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: peptide                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #1:                            - - Xaa Xaa Pro Asn Ala Leu Asn Phe Gly Gly Il - #e Gly Val Val Val         Gly                                                                               1               5  - #                 10 - #                 15              - - His Glu Leu Thr His Ala Phe                                                            20                                                                 - -  - - (2) INFORMATION FOR SEQ ID NO: 2:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 10 amino - #acids                                                  (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: peptide                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #2:                            - - Xaa Tyr Xaa Lys Xaa Gly Asn Leu Arg Pro                                    1               5  - #                 10                                      - -  - - (2) INFORMATION FOR SEQ ID NO: 3:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 10 amino - #acids                                                  (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: peptide                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #3:                            - - Xaa Ile Ala Xaa Glu Thr Xaa Xaa Glu Ile                                    1               5  - #                 10                                      - -  - - (2) INFORMATION FOR SEQ ID NO: 4:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 13 amino - #acids                                                  (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: peptide                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #4:                            - - Xaa Pro Glu Phe Leu Leu Glu Gly Leu Ile Th - #r Asp Pro                    1               5  - #                 10                                      - -  - - (2) INFORMATION FOR SEQ ID NO: 5:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 11 amino - #acids                                                  (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: peptide                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #5:                            - - Xaa Gln Ala Glu Asn Val Ile Gln Val Xaa Gl - #n                            1               5  - #                 10                                      - -  - - (2) INFORMATION FOR SEQ ID NO: 6:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 16 amino - #acids                                                  (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: peptide                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #6:                            - - Val Glu Ile Val Phe Pro Xaa Gly Ile Leu Gl - #n Ala Pro Phe Tyr Thr        1               5  - #                 10 - #                 15               - -  - - (2) INFORMATION FOR SEQ ID NO: 7:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 20 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #7:                            - - GGSCAYGARY TNACNCAYGC            - #                  - #                       - # 20                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO: 8:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 20 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #8:                            - - GARATYGTST TYCCYGCYGG            - #                  - #                       - # 20                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO: 9:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 23 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #9:                            - - ATYCTSCAGG CYCCYTTYTA YAC           - #                  - #                     23                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO: 10:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 45 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #10:                           - - CGAGGGGGAT GGTCGACGGA AGCGACCTTT TTTTTTTTTT TTTTT   - #                       - #45                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO: 11:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 19 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #11:                           - - CGAGGGGGAT GGTCGACGG             - #                  - #                       - # 19                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO: 12:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 20 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #12:                           - - GATGGTCGAC GGAAGCGACC            - #                  - #                       - # 20                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO:13:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 570 base - #pairs                                                  (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: cDNA for mRNA                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #13:                           - - ATC CTG CAG GCG CCA TTC TAC ACC CGC TCT TC - #A CCC AAT GCC TTA AAC            48                                                                        Ile Leu Gln Ala Pro Phe Tyr Thr Arg Ser Se - #r Pro Asn Ala Leu Asn             1               5  - #                 10 - #                 15               - - TTC GGC GGC ATC GGC GTC GTC GTG GGC CAC GA - #G CTG ACT CAT GCT TTT            96                                                                        Phe Gly Gly Ile Gly Val Val Val Gly His Gl - #u Leu Thr His Ala Phe                         20     - #             25     - #             30                   - - GAT GAT CAA GGC CGA GAG TAC GAC AAG GAT GG - #G AAC CTC CGG CCC TGG           144                                                                        Asp Asp Gln Gly Arg Glu Tyr Asp Lys Asp Gl - #y Asn Leu Arg Pro Trp                     35         - #         40         - #         45                       - - TGG AAG AAC TCG TCC GTG GAG GCG TTC AAG CA - #G CAG ACC GCG TGC ATG           192                                                                        Trp Lys Asn Ser Ser Val Glu Ala Phe Lys Gl - #n Gln Thr Ala Cys Met                 50             - #     55             - #     60                           - - GTG GAG CAG TAC GGC AAC TAT AGC GTG AAC GG - #G GAG CCG GTG AAC GGC           240                                                                        Val Glu Gln Tyr Gly Asn Tyr Ser Val Asn Gl - #y Glu Pro Val Asn Gly             65                 - # 70                 - # 75                 - # 80        - - CGG CAC ACC CTC GGC GAA AAC ATC GCC GAC AA - #C GGG GGC CTC AAG GCG           288                                                                        Arg His Thr Leu Gly Glu Asn Ile Ala Asp As - #n Gly Gly Leu Lys Ala                             85 - #                 90 - #                 95               - - GCC TAT CGG GCC TAC CAG AAC TGG GTC AAG AA - #G AAT GGG GCT GAG CAG           336                                                                        Ala Tyr Arg Ala Tyr Gln Asn Trp Val Lys Ly - #s Asn Gly Ala Glu Gln                        100      - #           105      - #           110                   - - ACA CTG CCC ACC CTG GGT CTC ACC AAC AAC CA - #G CTC TTC TTC CTG AGT           384                                                                        Thr Leu Pro Thr Leu Gly Leu Thr Asn Asn Gl - #n Leu Phe Phe Leu Ser                    115          - #       120          - #       125                       - - TTT GCA CAG GTC TGG TGT TCC GTC CGC ACC CC - #C GAG AGT TCG CAC GAA           432                                                                        Phe Ala Gln Val Trp Cys Ser Val Arg Thr Pr - #o Glu Ser Ser His Glu                130              - #   135              - #   140                           - - GGT CTC ATC ACC GAT CCC CAC AGC CCC TCC CG - #C TTC CGG GTC ATC GGC           480                                                                        Gly Leu Ile Thr Asp Pro His Ser Pro Ser Ar - #g Phe Arg Val Ile Gly            145                 1 - #50                 1 - #55                 1 -       #60                                                                               - - TCC ATC TCC AAC TCC AAG GAG TTC TCG GAA CA - #C TTC CAC TGC CCG         CCC      528                                                                     Ser Ile Ser Asn Ser Lys Glu Phe Ser Glu Hi - #s Phe His Cys Pro Pro                           165  - #               170  - #               175               - - GGC TCA CCC ATG AAC CCG CAT CAC AAG TGT GA - #A GTC TGG TGA                  - # 570                                                                     Gly Ser Pro Met Asn Pro His His Lys Cys Gl - #u Val Trp                                    180      - #           185                                          - -  - - (2) INFORMATION FOR SEQ ID NO: 14:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 189 amino - #acids                                                 (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: protein                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #14:                           - - Ile Leu Gln Ala Pro Phe Tyr Thr Arg Ser Se - #r Pro Asn Ala Leu Asn         1               5 - #                 10 - #                 15               - - Phe Gly Gly Ile Gly Val Val Val Gly His Gl - #u Leu Thr His Ala Phe                    20     - #             25     - #             30                   - - Asp Asp Gln Gly Arg Glu Tyr Asp Lys Asp Gl - #y Asn Leu Arg Pro Trp                35         - #         40         - #         45                       - - Trp Lys Asn Ser Ser Val Glu Ala Phe Lys Gl - #n Gln Thr Ala Cys Met            50             - #     55             - #     60                           - - Val Glu Gln Tyr Gly Asn Tyr Ser Val Asn Gl - #y Glu Pro Val Asn Gly        65                 - # 70                 - # 75                 - # 80        - - Arg His Thr Leu Gly Glu Asn Ile Ala Asp As - #n Gly Gly Leu Lys Ala                        85 - #                 90 - #                 95               - - Ala Tyr Arg Ala Tyr Gln Asn Trp Val Lys Ly - #s Asn Gly Ala Glu Gln                   100      - #           105      - #           110                   - - Thr Leu Pro Thr Leu Gly Leu Thr Asn Asn Gl - #n Leu Phe Phe Leu Ser               115          - #       120          - #       125                       - - Phe Ala Gln Val Trp Cys Ser Val Arg Thr Pr - #o Glu Ser Ser His Glu           130              - #   135              - #   140                           - - Gly Leu Ile Thr Asp Pro His Ser Pro Ser Ar - #g Phe Arg Val Ile Gly       145                 1 - #50                 1 - #55                 1 -       #60                                                                               - - Ser Ile Ser Asn Ser Lys Glu Phe Ser Glu Hi - #s Phe His Cys Pro         Pro                                                                                              165  - #               170  - #               175              - - Gly Ser Pro Met Asn Pro His His Lys Cys Gl - #u Val Trp                               180      - #           185                                          - -  - - (2) INFORMATION FOR SEQ ID NO: 15:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 27 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #15:                           - - GAGAGAGAGT CGACGGTACC NNNNNNN          - #                  - #                  27                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO: 16:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 21 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #16:                           - - CGGCCCTGGT GGAAGAACTC G           - #                  - #                       - #21                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO: 17:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 21 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #17:                           - - TGCGGACGGA ACACCAGACC T           - #                  - #                       - #21                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO: 18:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 1703 base - #pairs                                                 (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: cDNA for mRNA                                      - -  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #18:                      - - T GGC CAC TCG CGC TGG GGG ACC TTC AGC AAC - #CTC TGG GAA CAC AAC              46                                                                           Gly His Ser Arg Trp Gly Thr Phe Ser A - #sn Leu Trp Glu His Asn                  1              - # 5                 - # 10                 - # 15          - - CAA GCC ATC ATC AAG CAC CTC CTT GAA AAC TC - #C ACG GCC AGC GTG AGC            94                                                                        Gln Ala Ile Ile Lys His Leu Leu Glu Asn Se - #r Thr Ala Ser Val Ser                             20 - #                 25 - #                 30               - - GAG GCA GAG AGG AAG GAC CAG GAG TAC TAC CG - #A GCC TGC ATG AAC GAA           142                                                                        Glu Ala Glu Arg Lys Asp Gln Glu Tyr Tyr Ar - #g Ala Cys Met Asn Glu                         35     - #             40     - #             45                   - - ACC AGG ATT GAG GAG CTC AAG GCC AAA CCC CT - #G ATG GAG CTC ATT GAG           190                                                                        Thr Arg Ile Glu Glu Leu Lys Ala Lys Pro Le - #u Met Glu Leu Ile Glu                     50         - #         55         - #         60                       - - AAG CTC GGC GGC TGG AAC ATC ACG GGG CCC TG - #G GAC AAG GAC AAC TTC           238                                                                        Lys Leu Gly Gly Trp Asn Ile Thr Gly Pro Tr - #p Asp Lys Asp Asn Phe                 65             - #     70             - #     75                           - - CAG GAC ACC CTG CAG GTG GTC ACA TCC CAC TA - #C CAC ACC TCC CCC TTC           286                                                                        Gln Asp Thr Leu Gln Val Val Thr Ser His Ty - #r His Thr Ser Pro Phe             80                 - # 85                 - # 90                 - # 95        - - TTC TCC GTC TAC GTC AGT GCC GAC TCC AAG AA - #T TCC AAC AGC AAC GTG           334                                                                        Phe Ser Val Tyr Val Ser Ala Asp Ser Lys As - #n Ser Asn Ser Asn Val                            100  - #               105  - #               110               - - ATC CAA GTG GAC CAG TCT GGC CTG GGC TTA CC - #C TCA AGA GAT TAT TAC           382                                                                        Ile Gln Val Asp Gln Ser Gly Leu Gly Leu Pr - #o Ser Arg Asp Tyr Tyr                        115      - #           120      - #           125                   - - CTG AAC AAA ACC GAG AAT GAG AAG GTG CTG AC - #G GGA TAC CTG AAC TAC           430                                                                        Leu Asn Lys Thr Glu Asn Glu Lys Val Leu Th - #r Gly Tyr Leu Asn Tyr                    130          - #       135          - #       140                       - - ATG GTC CAG CTG GGG AAG CTG CTG GGA GGA GG - #G GCC GAG GAC ACC ATC           478                                                                        Met Val Gln Leu Gly Lys Leu Leu Gly Gly Gl - #y Ala Glu Asp Thr Ile                145              - #   150              - #   155                           - - CGG CCC CAG ATG CAG CAG ATC CTG GAC TTT GA - #G ACG GCG CTG GCC AAC           526                                                                        Arg Pro Gln Met Gln Gln Ile Leu Asp Phe Gl - #u Thr Ala Leu Ala Asn            160                 1 - #65                 1 - #70                 1 -       #75                                                                               - - ATC ACC ATC CCC CAG GAG AAG CGC CGG GAC GA - #G GAA CTC ATC TAC         CAC      574                                                                     Ile Thr Ile Pro Gln Glu Lys Arg Arg Asp Gl - #u Glu Leu Ile Tyr His                           180  - #               185  - #               190               - - AAA GTG ACG GCG GCT GAG TTG CAG ACC TTG GC - #G CCC GCC ATC AAC TGG           622                                                                        Lys Val Thr Ala Ala Glu Leu Gln Thr Leu Al - #a Pro Ala Ile Asn Trp                        195      - #           200      - #           205                   - - CTG CCC TTC CTC AAC ACC ATC TTC TAC CCC GT - #G GAG ATC AAT GAA TCA           670                                                                        Leu Pro Phe Leu Asn Thr Ile Phe Tyr Pro Va - #l Glu Ile Asn Glu Ser                    210          - #       215          - #       220                       - - GAG CCT ATT GTC ATC TAC GAC AAA GAA TAC CT - #G AGC AAG GTC TCC ACC           718                                                                        Glu Pro Ile Val Ile Tyr Asp Lys Glu Tyr Le - #u Ser Lys Val Ser Thr                225              - #   230              - #   235                           - - CTC ATC AAC AGC ACA GAC AAA TGC CTG CTG AA - #C AAC TAC ATG ATC TGG           766                                                                        Leu Ile Asn Ser Thr Asp Lys Cys Leu Leu As - #n Asn Tyr Met Ile Trp            240                 2 - #45                 2 - #50                 2 -       #55                                                                               - - AAC CTG GTA CGG AAG ACG AGC TCC TTC CTC GA - #T CAG CGC TTC CAG         GAC      814                                                                     Asn Leu Val Arg Lys Thr Ser Ser Phe Leu As - #p Gln Arg Phe Gln Asp                           260  - #               265  - #               270               - - GCC GAC GAG AAG TTC ATG GAA GTC ATG TAT GG - #G ACC AAG AAG ACG TGT           862                                                                        Ala Asp Glu Lys Phe Met Glu Val Met Tyr Gl - #y Thr Lys Lys Thr Cys                        275      - #           280      - #           285                   - - CTT CCC CGC TGG AAG TTT TGT GTG AGT GAT AC - #A GAG AAC ACC TTG GGC           910                                                                        Leu Pro Arg Trp Lys Phe Cys Val Ser Asp Th - #r Glu Asn Thr Leu Gly                    290          - #       295          - #       300                       - - TTC GCC CTG GGC CCC ATG TTC GTC AAA GCG AC - #C TTC GCT GAG GAC AGC           958                                                                        Phe Ala Leu Gly Pro Met Phe Val Lys Ala Th - #r Phe Ala Glu Asp Ser                305              - #   310              - #   315                           - - AAG AAC ATA GCC AGC GAG ATC ATC CTG GAG AT - #C AAG AAG GCG TTT GAA          1006                                                                        Lys Asn Ile Ala Ser Glu Ile Ile Leu Glu Il - #e Lys Lys Ala Phe Glu            320                 3 - #25                 3 - #30                 3 -       #35                                                                               - - GAG AGC CTG AGC ACC CTG AAG TGG ATG GAT GA - #A GAT ACT CGG AAA         TCG     1054                                                                     Glu Ser Leu Ser Thr Leu Lys Trp Met Asp Gl - #u Asp Thr Arg Lys Ser                           340  - #               345  - #               350               - - GCC AAG GAA AAG GCG GAC GCG ATC TAC AAC AT - #G ATA GGC TAC CCC AAC          1102                                                                        Ala Lys Glu Lys Ala Asp Ala Ile Tyr Asn Me - #t Ile Gly Tyr Pro Asn                        355      - #           360      - #           365                   - - TTT ATC ATG GAC CCC AAG GAG CTG GAC AAA GT - #G TTC AAT GAC TAC ACC          1150                                                                        Phe Ile Met Asp Pro Lys Glu Leu Asp Lys Va - #l Phe Asn Asp Tyr Thr                    370          - #       375          - #       380                       - - GCT GTG CCA GAC CTC TAC TTC GAG AAC GCC AT - #G CGG TTT TTC AAC TTC          1198                                                                        Ala Val Pro Asp Leu Tyr Phe Glu Asn Ala Me - #t Arg Phe Phe Asn Phe                385              - #   390              - #   395                           - - TCC TGG AGG GTC ACT GCC GAC CAG CTC CGG AA - #A GCG CCC AAC AGA GAT          1246                                                                        Ser Trp Arg Val Thr Ala Asp Gln Leu Arg Ly - #s Ala Pro Asn Arg Asp            400                 4 - #05                 4 - #10                 4 -       #15                                                                               - - CAG TGG AGC ATG ACC CCG CCC ATG GTG AAC GC - #C TAC TAC TCG CCC         ACC     1294                                                                     Gln Trp Ser Met Thr Pro Pro Met Val Asn Al - #a Tyr Tyr Ser Pro Thr                           420  - #               425  - #               430               - - AAG AAC GAG ATC GTG TTT CCG GCC GGA ATC CT - #G CAG GCG CCA TTC TAC          1342                                                                        Lys Asn Glu Ile Val Phe Pro Ala Gly Ile Le - #u Gln Ala Pro Phe Tyr                        435      - #           440      - #           445                   - - ACC CGC TCT TCA CCC AAT GCC TTA AAC TTC GG - #C GGC ATC GGC GTC GTC          1390                                                                        Thr Arg Ser Ser Pro Asn Ala Leu Asn Phe Gl - #y Gly Ile Gly Val Val                    450          - #       455          - #       460                       - - GTG GGC CAC GAG CTG ACT CAT GCT TTT GAT GA - #T CAA GGC CGA GAG TAC          1438                                                                        Val Gly His Glu Leu Thr His Ala Phe Asp As - #p Gln Gly Arg Glu Tyr                465              - #   470              - #   475                           - - GAC AAG GAT GGG AAC CTC CGG CCC TGG TGG AA - #G AAC TCG TCC GTG GAG          1486                                                                        Asp Lys Asp Gly Asn Leu Arg Pro Trp Trp Ly - #s Asn Ser Ser Val Glu            480                 4 - #85                 4 - #90                 4 -       #95                                                                               - - GCG TTC AAG CAG CAG ACC GCG TGC ATG GTG GA - #G CAG TAC GGC AAC         TAT     1534                                                                     Ala Phe Lys Gln Gln Thr Ala Cys Met Val Gl - #u Gln Tyr Gly Asn Tyr                           500  - #               505  - #               510               - - AGC GTG AAC GGG GAG CCG GTG AAC GGC CGG CA - #C ACC CTC GGC GAA AAC          1582                                                                        Ser Val Asn Gly Glu Pro Val Asn Gly Arg Hi - #s Thr Leu Gly Glu Asn                        515      - #           520      - #           525                   - - ATC GCC GAC AAC GGG GGC CTC AAG GCG GCC TA - #T CGG GCC TAC CAG AAC          1630                                                                        Ile Ala Asp Asn Gly Gly Leu Lys Ala Ala Ty - #r Arg Ala Tyr Gln Asn                    530          - #       535          - #       540                       - - TGG GTC AAG AAG AAT GGG GCT GAG CAG ACA CT - #G CCC ACC CTG GGT CTC          1678                                                                        Trp Val Lys Lys Asn Gly Ala Glu Gln Thr Le - #u Pro Thr Leu Gly Leu                545              - #   550              - #   555                           - - ACC AAC AAC CAG CTC TTC TTC CTG A    - #                  - #                  1703                                                                      Thr Asn Asn Gln Leu Phe Phe Leu                                                560                 5 - #65                                                     - -  - - (2) INFORMATION FOR SEQ ID NO: 19:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 567 amino - #acids                                                 (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: protein                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #19:                           - - Gly His Ser Arg Trp Gly Thr Phe Ser Asn Le - #u Trp Glu His Asn Gln         1               5 - #                 10 - #                 15               - - Ala Ile Ile Lys His Leu Leu Glu Asn Ser Th - #r Ala Ser Val Ser Glu                    20     - #             25     - #             30                   - - Ala Glu Arg Lys Asp Gln Glu Tyr Tyr Arg Al - #a Cys Met Asn Glu Thr                35         - #         40         - #         45                       - - Arg Ile Glu Glu Leu Lys Ala Lys Pro Leu Me - #t Glu Leu Ile Glu Lys            50             - #     55             - #     60                           - - Leu Gly Gly Trp Asn Ile Thr Gly Pro Trp As - #p Lys Asp Asn Phe Gln        65                 - # 70                 - # 75                 - # 80        - - Asp Thr Leu Gln Val Val Thr Ser His Tyr Hi - #s Thr Ser Pro Phe Phe                        85 - #                 90 - #                 95               - - Ser Val Tyr Val Ser Ala Asp Ser Lys Asn Se - #r Asn Ser Asn Val Ile                   100      - #           105      - #           110                   - - Gln Val Asp Gln Ser Gly Leu Gly Leu Pro Se - #r Arg Asp Tyr Tyr Leu               115          - #       120          - #       125                       - - Asn Lys Thr Glu Asn Glu Lys Val Leu Thr Gl - #y Tyr Leu Asn Tyr Met           130              - #   135              - #   140                           - - Val Gln Leu Gly Lys Leu Leu Gly Gly Gly Al - #a Glu Asp Thr Ile Arg       145                 1 - #50                 1 - #55                 1 -       #60                                                                               - - Pro Gln Met Gln Gln Ile Leu Asp Phe Glu Th - #r Ala Leu Ala Asn         Ile                                                                                              165  - #               170  - #               175              - - Thr Ile Pro Gln Glu Lys Arg Arg Asp Glu Gl - #u Leu Ile Tyr His Lys                   180      - #           185      - #           190                   - - Val Thr Ala Ala Glu Leu Gln Thr Leu Ala Pr - #o Ala Ile Asn Trp Leu               195          - #       200          - #       205                       - - Pro Phe Leu Asn Thr Ile Phe Tyr Pro Val Gl - #u Ile Asn Glu Ser Glu           210              - #   215              - #   220                           - - Pro Ile Val Ile Tyr Asp Lys Glu Tyr Leu Se - #r Lys Val Ser Thr Leu       225                 2 - #30                 2 - #35                 2 -       #40                                                                               - - Ile Asn Ser Thr Asp Lys Cys Leu Leu Asn As - #n Tyr Met Ile Trp         Asn                                                                                              245  - #               250  - #               255              - - Leu Val Arg Lys Thr Ser Ser Phe Leu Asp Gl - #n Arg Phe Gln Asp Ala                   260      - #           265      - #           270                   - - Asp Glu Lys Phe Met Glu Val Met Tyr Gly Th - #r Lys Lys Thr Cys Leu               275          - #       280          - #       285                       - - Pro Arg Trp Lys Phe Cys Val Ser Asp Thr Gl - #u Asn Thr Leu Gly Phe           290              - #   295              - #   300                           - - Ala Leu Gly Pro Met Phe Val Lys Ala Thr Ph - #e Ala Glu Asp Ser Lys       305                 3 - #10                 3 - #15                 3 -       #20                                                                               - - Asn Ile Ala Ser Glu Ile Ile Leu Glu Ile Ly - #s Lys Ala Phe Glu         Glu                                                                                              325  - #               330  - #               335              - - Ser Leu Ser Thr Leu Lys Trp Met Asp Glu As - #p Thr Arg Lys Ser Ala                   340      - #           345      - #           350                   - - Lys Glu Lys Ala Asp Ala Ile Tyr Asn Met Il - #e Gly Tyr Pro Asn Phe               355          - #       360          - #       365                       - - Ile Met Asp Pro Lys Glu Leu Asp Lys Val Ph - #e Asn Asp Tyr Thr Ala           370              - #   375              - #   380                           - - Val Pro Asp Leu Tyr Phe Glu Asn Ala Met Ar - #g Phe Phe Asn Phe Ser       385                 3 - #90                 3 - #95                 4 -       #00                                                                               - - Trp Arg Val Thr Ala Asp Gln Leu Arg Lys Al - #a Pro Asn Arg Asp         Gln                                                                                              405  - #               410  - #               415              - - Trp Ser Met Thr Pro Pro Met Val Asn Ala Ty - #r Tyr Ser Pro Thr Lys                   420      - #           425      - #           430                   - - Asn Glu Ile Val Phe Pro Ala Gly Ile Leu Gl - #n Ala Pro Phe Tyr Thr               435          - #       440          - #       445                       - - Arg Ser Ser Pro Asn Ala Leu Asn Phe Gly Gl - #y Ile Gly Val Val Val           450              - #   455              - #   460                           - - Gly His Glu Leu Thr His Ala Phe Asp Asp Gl - #n Gly Arg Glu Tyr Asp       465                 4 - #70                 4 - #75                 4 -       #80                                                                               - - Lys Asp Gly Asn Leu Arg Pro Trp Trp Lys As - #n Ser Ser Val Glu         Ala                                                                                              485  - #               490  - #               495              - - Phe Lys Gln Gln Thr Ala Cys Met Val Glu Gl - #n Tyr Gly Asn Tyr Ser                   500      - #           505      - #           510                   - - Val Asn Gly Glu Pro Val Asn Gly Arg His Th - #r Leu Gly Glu Asn Ile               515          - #       520          - #       525                       - - Ala Asp Asn Gly Gly Leu Lys Ala Ala Tyr Ar - #g Ala Tyr Gln Asn Trp           530              - #   535              - #   540                           - - Val Lys Lys Asn Gly Ala Glu Gln Thr Leu Pr - #o Thr Leu Gly Leu Thr       545                 5 - #50                 5 - #55                 5 -       #60                                                                               - - Asn Asn Gln Leu Phe Phe Leu                                                               565                                                             - -  - - (2) INFORMATION FOR SEQ ID NO: 20:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 23 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #20:                           - - GCCAGCGCCG TCTCAAAGTC CAG           - #                  - #                     23                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO: 21:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 22 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #21:                           - - TGGGGGACCT TCAGCAACCT CT           - #                  - #                      22                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO: 22:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 2129 base - #pairs                                                 (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: cDNA for mRNA                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #22:                           - - GG ACC CCG GTG GAG AAG CGG CTG GTG GTG CTG - # GTG GCG CTC CTG GCG             47                                                                           Thr Pro Val Glu Lys Arg Leu Val Val - #Leu Val Ala Leu Leu Ala                   1             - #  5                - #  10                - #  15         - - GCG GCA TTG GTG GCC TGT TTG GCA GTA CTG GG - #C ATC CAA TAC CAG ACA            95                                                                        Ala Ala Leu Val Ala Cys Leu Ala Val Leu Gl - #y Ile Gln Tyr Gln Thr                             20 - #                 25 - #                 30               - - AGA ACG CCC TCG GTG TGC CTA AGT GAG GCC TG - #C ATC TCG GTG ACC AGC           143                                                                        Arg Thr Pro Ser Val Cys Leu Ser Glu Ala Cy - #s Ile Ser Val Thr Ser                         35     - #             40     - #             45                   - - TCC ATC TTG AGT TCC ATG GAC CCC ACG GTG GA - #C CCC TGC CAG GAC TTC           191                                                                        Ser Ile Leu Ser Ser Met Asp Pro Thr Val As - #p Pro Cys Gln Asp Phe                     50         - #         55         - #         60                       - - TTC ACC TAT GCC TGT GGC GGC TGG ATC AAA GC - #C AAC CCC GTG CCG GAT           239                                                                        Phe Thr Tyr Ala Cys Gly Gly Trp Ile Lys Al - #a Asn Pro Val Pro Asp                 65             - #     70             - #     75                           - - GGC CAC TCG CGC TGG GGG ACC TTC AGC AAC CT - #C TGG GAA CAC AAC CAA           287                                                                        Gly His Ser Arg Trp Gly Thr Phe Ser Asn Le - #u Trp Glu His Asn Gln             80                 - # 85                 - # 90                 - # 95        - - GCC ATC ATC AAG CAC CTC CTT GAA AAC TCC AC - #G GCC AGC GTG AGC GAG           335                                                                        Ala Ile Ile Lys His Leu Leu Glu Asn Ser Th - #r Ala Ser Val Ser Glu                            100  - #               105  - #               110               - - GCA GAG AGG AAG GAC CAG GAG TAC TAC CGA GC - #C TGC ATG AAC GAA ACC           383                                                                        Ala Glu Arg Lys Asp Gln Glu Tyr Tyr Arg Al - #a Cys Met Asn Glu Thr                        115      - #           120      - #           125                   - - AGG ATT GAG GAG CTC AAG GCC AAA CCC CTG AT - #G GAG CTC ATT GAG AAG           431                                                                        Arg Ile Glu Glu Leu Lys Ala Lys Pro Leu Me - #t Glu Leu Ile Glu Lys                    130          - #       135          - #       140                       - - CTC GGC GGC TGG AAC ATC ACG GGG CCC TGG GA - #C AAG GAC AAC TTC CAG           479                                                                        Leu Gly Gly Trp Asn Ile Thr Gly Pro Trp As - #p Lys Asp Asn Phe Gln                145              - #   150              - #   155                           - - GAC ACC CTG CAG GTG GTC ACA TCC CAC TAC CA - #C ACC TCC CCC TTC TTC           527                                                                        Asp Thr Leu Gln Val Val Thr Ser His Tyr Hi - #s Thr Ser Pro Phe Phe            160                 1 - #65                 1 - #70                 1 -       #75                                                                               - - TCC GTC TAC GTC AGT GCC GAC TCC AAG AAT TC - #C AAC AGC AAC GTG         ATC      575                                                                     Ser Val Tyr Val Ser Ala Asp Ser Lys Asn Se - #r Asn Ser Asn Val Ile                           180  - #               185  - #               190               - - CAA GTG GAC CAG TCT GGC CTG GGC TTA CCC TC - #A AGA GAT TAT TAC CTG           623                                                                        Gln Val Asp Gln Ser Gly Leu Gly Leu Pro Se - #r Arg Asp Tyr Tyr Leu                        195      - #           200      - #           205                   - - AAC AAA ACC GAG AAT GAG AAG GTG CTG ACG GG - #A TAC CTG AAC TAC ATG           671                                                                        Asn Lys Thr Glu Asn Glu Lys Val Leu Thr Gl - #y Tyr Leu Asn Tyr Met                    210          - #       215          - #       220                       - - GTC CAG CTG GGG AAG CTG CTG GGA GGA GGG GC - #C GAG GAC ACC ATC CGG           719                                                                        Val Gln Leu Gly Lys Leu Leu Gly Gly Gly Al - #a Glu Asp Thr Ile Arg                225              - #   230              - #   235                           - - CCC CAG ATG CAG CAG ATC CTG GAC TTT GAG AC - #G GCG CTG GCC AAC ATC           767                                                                        Pro Gln Met Gln Gln Ile Leu Asp Phe Glu Th - #r Ala Leu Ala Asn Ile            240                 2 - #45                 2 - #50                 2 -       #55                                                                               - - ACC ATC CCC CAG GAG AAG CGC CGG GAC GAG GA - #A CTC ATC TAC CAC         AAA      815                                                                     Thr Ile Pro Gln Glu Lys Arg Arg Asp Glu Gl - #u Leu Ile Tyr His Lys                           260  - #               265  - #               270               - - GTG ACG GCG GCT GAG TTG CAG ACC TTG GCG CC - #C GCC ATC AAC TGG CTG           863                                                                        Val Thr Ala Ala Glu Leu Gln Thr Leu Ala Pr - #o Ala Ile Asn Trp Leu                        275      - #           280      - #           285                   - - CCC TTC CTC AAC ACC ATC TTC TAC CCC GTG GA - #G ATC AAT GAA TCA GAG           911                                                                        Pro Phe Leu Asn Thr Ile Phe Tyr Pro Val Gl - #u Ile Asn Glu Ser Glu                    290          - #       295          - #       300                       - - CCT ATT GTC ATC TAC GAC AAA GAA TAC CTG AG - #C AAG GTC TCC ACC CTC           959                                                                        Pro Ile Val Ile Tyr Asp Lys Glu Tyr Leu Se - #r Lys Val Ser Thr Leu                305              - #   310              - #   315                           - - ATC AAC AGC ACA GAC AAA TGC CTG CTG AAC AA - #C TAC ATG ATC TGG AAC          1007                                                                        Ile Asn Ser Thr Asp Lys Cys Leu Leu Asn As - #n Tyr Met Ile Trp Asn            320                 3 - #25                 3 - #30                 3 -       #35                                                                               - - CTG GTA CGG AAG ACG AGC TCC TTC CTC GAT CA - #G CGC TTC CAG GAC         GCC     1055                                                                     Leu Val Arg Lys Thr Ser Ser Phe Leu Asp Gl - #n Arg Phe Gln Asp Ala                           340  - #               345  - #               350               - - GAC GAG AAG TTC ATG GAA GTC ATG TAT GGG AC - #C AAG AAG ACG TGT CTT          1103                                                                        Asp Glu Lys Phe Met Glu Val Met Tyr Gly Th - #r Lys Lys Thr Cys Leu                        355      - #           360      - #           365                   - - CCC CGC TGG AAG TTT TGT GTG AGT GAT ACA GA - #G AAC ACC TTG GGC TTC          1151                                                                        Pro Arg Trp Lys Phe Cys Val Ser Asp Thr Gl - #u Asn Thr Leu Gly Phe                    370          - #       375          - #       380                       - - GCC CTG GGC CCC ATG TTC GTC AAA GCG ACC TT - #C GCT GAG GAC AGC AAG          1199                                                                        Ala Leu Gly Pro Met Phe Val Lys Ala Thr Ph - #e Ala Glu Asp Ser Lys                385              - #   390              - #   395                           - - AAC ATA GCC AGC GAG ATC ATC CTG GAG ATC AA - #G AAG GCG TTT GAA GAG          1247                                                                        Asn Ile Ala Ser Glu Ile Ile Leu Glu Ile Ly - #s Lys Ala Phe Glu Glu            400                 4 - #05                 4 - #10                 4 -       #15                                                                               - - AGC CTG AGC ACC CTG AAG TGG ATG GAT GAA GA - #T ACT CGG AAA TCG         GCC     1295                                                                     Ser Leu Ser Thr Leu Lys Trp Met Asp Glu As - #p Thr Arg Lys Ser Ala                           420  - #               425  - #               430               - - AAG GAA AAG GCG GAC GCG ATC TAC AAC ATG AT - #A GGC TAC CCC AAC TTT          1343                                                                        Lys Glu Lys Ala Asp Ala Ile Tyr Asn Met Il - #e Gly Tyr Pro Asn Phe                        435      - #           440      - #           445                   - - ATC ATG GAC CCC AAG GAG CTG GAC AAA GTG TT - #C AAT GAC TAC ACC GCT          1391                                                                        Ile Met Asp Pro Lys Glu Leu Asp Lys Val Ph - #e Asn Asp Tyr Thr Ala                    450          - #       455          - #       460                       - - GTG CCA GAC CTC TAC TTC GAG AAC GCC ATG CG - #G TTT TTC AAC TTC TCC          1439                                                                        Val Pro Asp Leu Tyr Phe Glu Asn Ala Met Ar - #g Phe Phe Asn Phe Ser                465              - #   470              - #   475                           - - TGG AGG GTC ACT GCC GAC CAG CTC CGG AAA GC - #G CCC AAC AGA GAT CAG          1487                                                                        Trp Arg Val Thr Ala Asp Gln Leu Arg Lys Al - #a Pro Asn Arg Asp Gln            480                 4 - #85                 4 - #90                 4 -       #95                                                                               - - TGG AGC ATG ACC CCG CCC ATG GTG AAC GCC TA - #C TAC TCG CCC ACC         AAG     1535                                                                     Trp Ser Met Thr Pro Pro Met Val Asn Ala Ty - #r Tyr Ser Pro Thr Lys                           500  - #               505  - #               510               - - AAC GAG ATC GTG TTT CCG GCC GGA ATC CTG CA - #G GCG CCA TTC TAC ACC          1583                                                                        Asn Glu Ile Val Phe Pro Ala Gly Ile Leu Gl - #n Ala Pro Phe Tyr Thr                        515      - #           520      - #           525                   - - CGC TCT TCA CCC AAT GCC TTA AAC TTC GGC GG - #C ATC GGC GTC GTC GTG          1631                                                                        Arg Ser Ser Pro Asn Ala Leu Asn Phe Gly Gl - #y Ile Gly Val Val Val                    530          - #       535          - #       540                       - - GGC CAC GAG CTG ACT CAT GCT TTT GAT GAT CA - #A GGC CGA GAG TAC GAC          1679                                                                        Gly His Glu Leu Thr His Ala Phe Asp Asp Gl - #n Gly Arg Glu Tyr Asp                545              - #   550              - #   555                           - - AAG GAT GGG AAC CTC CGG CCC TGG TGG AAG AA - #C TCG TCC GTG GAG GCG          1727                                                                        Lys Asp Gly Asn Leu Arg Pro Trp Trp Lys As - #n Ser Ser Val Glu Ala            560                 5 - #65                 5 - #70                 5 -       #75                                                                               - - TTC AAG CAG CAG ACC GCG TGC ATG GTG GAG CA - #G TAC GGC AAC TAT         AGC     1775                                                                     Phe Lys Gln Gln Thr Ala Cys Met Val Glu Gl - #n Tyr Gly Asn Tyr Ser                           580  - #               585  - #               590               - - GTG AAC GGG GAG CCG GTG AAC GGC CGG CAC AC - #C CTC GGC GAA AAC ATC          1823                                                                        Val Asn Gly Glu Pro Val Asn Gly Arg His Th - #r Leu Gly Glu Asn Ile                        595      - #           600      - #           605                   - - GCC GAC AAC GGG GGC CTC AAG GCG GCC TAT CG - #G GCC TAC CAG AAC TGG          1871                                                                        Ala Asp Asn Gly Gly Leu Lys Ala Ala Tyr Ar - #g Ala Tyr Gln Asn Trp                    610          - #       615          - #       620                       - - GTC AAG AAG AAT GGG GCT GAG CAG ACA CTG CC - #C ACC CTG GGT CTC ACC          1919                                                                        Val Lys Lys Asn Gly Ala Glu Gln Thr Leu Pr - #o Thr Leu Gly Leu Thr                625              - #   630              - #   635                           - - AAC AAC CAG CTC TTC TTC CTG AGT TTT GCA CA - #G GTC TGG TGT TCC GTC          1967                                                                        Asn Asn Gln Leu Phe Phe Leu Ser Phe Ala Gl - #n Val Trp Cys Ser Val            640                 6 - #45                 6 - #50                 6 -       #55                                                                               - - CGC ACC CCC GAG AGT TCG CAC GAA GGT CTC AT - #C ACC GAT CCC CAC         AGC     2015                                                                     Arg Thr Pro Glu Ser Ser His Glu Gly Leu Il - #e Thr Asp Pro His Ser                           660  - #               665  - #               670               - - CCC TCC CGC TTC CGG GTC ATC GGC TCC ATC TC - #C AAC TCC AAG GAG TTC          2063                                                                        Pro Ser Arg Phe Arg Val Ile Gly Ser Ile Se - #r Asn Ser Lys Glu Phe                        675      - #           680      - #           685                   - - TCG GAA CAC TTC CAC TGC CCG CCC GGC TCA CC - #C ATG AAC CCG CAT CAC          2111                                                                        Ser Glu His Phe His Cys Pro Pro Gly Ser Pr - #o Met Asn Pro His His                    690          - #       695          - #       700                       - - AAG TGT GAA GTC TGG TGA         - #                  - #                       - #2129                                                                   Lys Cys Glu Val Trp                                                                705                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO: 23:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 708 amino - #acids                                                 (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: protein                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #23:                           - - Thr Pro Val Glu Lys Arg Leu Val Val Leu Va - #l Ala Leu Leu Ala Ala         1               5 - #                 10 - #                 15               - - Ala Leu Val Ala Cys Leu Ala Val Leu Gly Il - #e Gln Tyr Gln Thr Arg                    20     - #             25     - #             30                   - - Thr Pro Ser Val Cys Leu Ser Glu Ala Cys Il - #e Ser Val Thr Ser Ser                35         - #         40         - #         45                       - - Ile Leu Ser Ser Met Asp Pro Thr Val Asp Pr - #o Cys Gln Asp Phe Phe            50             - #     55             - #     60                           - - Thr Tyr Ala Cys Gly Gly Trp Ile Lys Ala As - #n Pro Val Pro Asp Gly        65                 - # 70                 - # 75                 - # 80        - - His Ser Arg Trp Gly Thr Phe Ser Asn Leu Tr - #p Glu His Asn Gln Ala                        85 - #                 90 - #                 95               - - Ile Ile Lys His Leu Leu Glu Asn Ser Thr Al - #a Ser Val Ser Glu Ala                   100      - #           105      - #           110                   - - Glu Arg Lys Asp Gln Glu Tyr Tyr Arg Ala Cy - #s Met Asn Glu Thr Arg               115          - #       120          - #       125                       - - Ile Glu Glu Leu Lys Ala Lys Pro Leu Met Gl - #u Leu Ile Glu Lys Leu           130              - #   135              - #   140                           - - Gly Gly Trp Asn Ile Thr Gly Pro Trp Asp Ly - #s Asp Asn Phe Gln Asp       145                 1 - #50                 1 - #55                 1 -       #60                                                                               - - Thr Leu Gln Val Val Thr Ser His Tyr His Th - #r Ser Pro Phe Phe         Ser                                                                                              165  - #               170  - #               175              - - Val Tyr Val Ser Ala Asp Ser Lys Asn Ser As - #n Ser Asn Val Ile Gln                   180      - #           185      - #           190                   - - Val Asp Gln Ser Gly Leu Gly Leu Pro Ser Ar - #g Asp Tyr Tyr Leu Asn               195          - #       200          - #       205                       - - Lys Thr Glu Asn Glu Lys Val Leu Thr Gly Ty - #r Leu Asn Tyr Met Val           210              - #   215              - #   220                           - - Gln Leu Gly Lys Leu Leu Gly Gly Gly Ala Gl - #u Asp Thr Ile Arg Pro       225                 2 - #30                 2 - #35                 2 -       #40                                                                               - - Gln Met Gln Gln Ile Leu Asp Phe Glu Thr Al - #a Leu Ala Asn Ile         Thr                                                                                              245  - #               250  - #               255              - - Ile Pro Gln Glu Lys Arg Arg Asp Glu Glu Le - #u Ile Tyr His Lys Val                   260      - #           265      - #           270                   - - Thr Ala Ala Glu Leu Gln Thr Leu Ala Pro Al - #a Ile Asn Trp Leu Pro               275          - #       280          - #       285                       - - Phe Leu Asn Thr Ile Phe Tyr Pro Val Glu Il - #e Asn Glu Ser Glu Pro           290              - #   295              - #   300                           - - Ile Val Ile Tyr Asp Lys Glu Tyr Leu Ser Ly - #s Val Ser Thr Leu Ile       305                 3 - #10                 3 - #15                 3 -       #20                                                                               - - Asn Ser Thr Asp Lys Cys Leu Leu Asn Asn Ty - #r Met Ile Trp Asn         Leu                                                                                              325  - #               330  - #               335              - - Val Arg Lys Thr Ser Ser Phe Leu Asp Gln Ar - #g Phe Gln Asp Ala Asp                   340      - #           345      - #           350                   - - Glu Lys Phe Met Glu Val Met Tyr Gly Thr Ly - #s Lys Thr Cys Leu Pro               355          - #       360          - #       365                       - - Arg Trp Lys Phe Cys Val Ser Asp Thr Glu As - #n Thr Leu Gly Phe Ala           370              - #   375              - #   380                           - - Leu Gly Pro Met Phe Val Lys Ala Thr Phe Al - #a Glu Asp Ser Lys Asn       385                 3 - #90                 3 - #95                 4 -       #00                                                                               - - Ile Ala Ser Glu Ile Ile Leu Glu Ile Lys Ly - #s Ala Phe Glu Glu         Ser                                                                                              405  - #               410  - #               415              - - Leu Ser Thr Leu Lys Trp Met Asp Glu Asp Th - #r Arg Lys Ser Ala Lys                   420      - #           425      - #           430                   - - Glu Lys Ala Asp Ala Ile Tyr Asn Met Ile Gl - #y Tyr Pro Asn Phe Ile               435          - #       440          - #       445                       - - Met Asp Pro Lys Glu Leu Asp Lys Val Phe As - #n Asp Tyr Thr Ala Val           450              - #   455              - #   460                           - - Pro Asp Leu Tyr Phe Glu Asn Ala Met Arg Ph - #e Phe Asn Phe Ser Trp       465                 4 - #70                 4 - #75                 4 -       #80                                                                               - - Arg Val Thr Ala Asp Gln Leu Arg Lys Ala Pr - #o Asn Arg Asp Gln         Trp                                                                                              485  - #               490  - #               495              - - Ser Met Thr Pro Pro Met Val Asn Ala Tyr Ty - #r Ser Pro Thr Lys Asn                   500      - #           505      - #           510                   - - Glu Ile Val Phe Pro Ala Gly Ile Leu Gln Al - #a Pro Phe Tyr Thr Arg               515          - #       520          - #       525                       - - Ser Ser Pro Asn Ala Leu Asn Phe Gly Gly Il - #e Gly Val Val Val Gly           530              - #   535              - #   540                           - - His Glu Leu Thr His Ala Phe Asp Asp Gln Gl - #y Arg Glu Tyr Asp Lys       545                 5 - #50                 5 - #55                 5 -       #60                                                                               - - Asp Gly Asn Leu Arg Pro Trp Trp Lys Asn Se - #r Ser Val Glu Ala         Phe                                                                                              565  - #               570  - #               575              - - Lys Gln Gln Thr Ala Cys Met Val Glu Gln Ty - #r Gly Asn Tyr Ser Val                   580      - #           585      - #           590                   - - Asn Gly Glu Pro Val Asn Gly Arg His Thr Le - #u Gly Glu Asn Ile Ala               595          - #       600          - #       605                       - - Asp Asn Gly Gly Leu Lys Ala Ala Tyr Arg Al - #a Tyr Gln Asn Trp Val           610              - #   615              - #   620                           - - Lys Lys Asn Gly Ala Glu Gln Thr Leu Pro Th - #r Leu Gly Leu Thr Asn       625                 6 - #30                 6 - #35                 6 -       #40                                                                               - - Asn Gln Leu Phe Phe Leu Ser Phe Ala Gln Va - #l Trp Cys Ser Val         Arg                                                                                              645  - #               650  - #               655              - - Thr Pro Glu Ser Ser His Glu Gly Leu Ile Th - #r Asp Pro His Ser Pro                   660      - #           665      - #           670                   - - Ser Arg Phe Arg Val Ile Gly Ser Ile Ser As - #n Ser Lys Glu Phe Ser               675          - #       680          - #       685                       - - Glu His Phe His Cys Pro Pro Gly Ser Pro Me - #t Asn Pro His His Lys           690              - #   695              - #   700                           - - Cys Glu Val Trp                                                           705                                                                             - -  - - (2) INFORMATION FOR SEQ ID NO: 24:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 2533 base - #pairs                                                 (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: cDNA for mRNA                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #24:                           - - CGG CTG GTG GTG TTG GTG GTA CTT CTG GCG GC - #A GGA CTG GTG GCC TGC            48                                                                        Arg Leu Val Val Leu Val Val Leu Leu Ala Al - #a Gly Leu Val Ala Cys              1               5 - #                 10 - #                 15               - - TTG GCA GCA CTG GGC ATC CAG TAC CAG ACA AG - #A TCC CCC TCT GTG TGC            96                                                                        Leu Ala Ala Leu Gly Ile Gln Tyr Gln Thr Ar - #g Ser Pro Ser Val Cys                         20     - #             25     - #             30                   - - CTG AGC GAA GCT TGT GTC TCA GTG ACC AGC TC - #C ATC TTG AGC TCC ATG           144                                                                        Leu Ser Glu Ala Cys Val Ser Val Thr Ser Se - #r Ile Leu Ser Ser Met                     35         - #         40         - #         45                       - - GAC CCC ACA GTG GAC CCC TGC CAT GAC TTC TT - #C AGC TAC GCC TGT GGG           192                                                                        Asp Pro Thr Val Asp Pro Cys His Asp Phe Ph - #e Ser Tyr Ala Cys Gly                 50             - #     55             - #     60                           - - GGC TGG ATC AAG GCC AAC CCA GTC CCT GAT GG - #C CAC TCA CGC TGG GGG           240                                                                        Gly Trp Ile Lys Ala Asn Pro Val Pro Asp Gl - #y His Ser Arg Trp Gly             65                 - # 70                 - # 75                 - # 80        - - ACC TTC AGC AAC CTC TGG GAA CAC AAC CAA GC - #A ATC ATC AAG CAC CTC           288                                                                        Thr Phe Ser Asn Leu Trp Glu His Asn Gln Al - #a Ile Ile Lys His Leu                             85 - #                 90 - #                 95               - - CTC GAA AAC TCC ACG GCC AGC GTG AGC GAG GC - #A GAG AGA AAG GCG CAA           336                                                                        Leu Glu Asn Ser Thr Ala Ser Val Ser Glu Al - #a Glu Arg Lys Ala Gln                        100      - #           105      - #           110                   - - GTA TAC TAC CGT GCG TGC ATG AAC GAG ACC AG - #G ATC GAG GAG CTC AGG           384                                                                        Val Tyr Tyr Arg Ala Cys Met Asn Glu Thr Ar - #g Ile Glu Glu Leu Arg                    115          - #       120          - #       125                       - - GCC AAA CCT CTA ATG GAG TTG ATT GAG AGG CT - #C GGG GGC TGG AAC ATC           432                                                                        Ala Lys Pro Leu Met Glu Leu Ile Glu Arg Le - #u Gly Gly Trp Asn Ile                130              - #   135              - #   140                           - - ACA GGT CCC TGG GCC AAG GAC AAC TTC CAG GA - #C ACC CTG CAG GTG GTC           480                                                                        Thr Gly Pro Trp Ala Lys Asp Asn Phe Gln As - #p Thr Leu Gln Val Val            145                 1 - #50                 1 - #55                 1 -       #60                                                                               - - ACC GCC CAC TAC CGC ACC TCA CCC TTC TTC TC - #T GTC TAT GTC AGT         GCC      528                                                                     Thr Ala His Tyr Arg Thr Ser Pro Phe Phe Se - #r Val Tyr Val Ser Ala                           165  - #               170  - #               175               - - GAT TCC AAG AAC TCC AAC AGC AAC GTG ATC CA - #G GTG GAC CAG TCT GGC           576                                                                        Asp Ser Lys Asn Ser Asn Ser Asn Val Ile Gl - #n Val Asp Gln Ser Gly                        180      - #           185      - #           190                   - - CTG GGC TTG CCC TCG AGA GAC TAT TAC CTG AA - #C AAA ACT GAA AAC GAG           624                                                                        Leu Gly Leu Pro Ser Arg Asp Tyr Tyr Leu As - #n Lys Thr Glu Asn Glu                    195          - #       200          - #       205                       - - AAG GTG CTG ACC GGA TAT CTG AAC TAC ATG GT - #C CAG CTG GGG AAG CTG           672                                                                        Lys Val Leu Thr Gly Tyr Leu Asn Tyr Met Va - #l Gln Leu Gly Lys Leu                210              - #   215              - #   220                           - - CTG GGC GGC GGG GAC GAG GAG GCC ATC CGG CC - #C CAG ATG CAG CAG ATC           720                                                                        Leu Gly Gly Gly Asp Glu Glu Ala Ile Arg Pr - #o Gln Met Gln Gln Ile            225                 2 - #30                 2 - #35                 2 -       #40                                                                               - - TTG GAC TTT GAG ACG GCA CTG GCC AAC ATC AC - #C ATC CCA CAG GAG         AAG      768                                                                     Leu Asp Phe Glu Thr Ala Leu Ala Asn Ile Th - #r Ile Pro Gln Glu Lys                           245  - #               250  - #               255               - - CGC CGT GAT GAG GAG CTC ATC TAC CAC AAA GT - #G ACG GCA GCC GAG CTG           816                                                                        Arg Arg Asp Glu Glu Leu Ile Tyr His Lys Va - #l Thr Ala Ala Glu Leu                        260      - #           265      - #           270                   - - CAG ACC TTG GCA CCC GCC ATC AAC TGG TTG CC - #T TTT CTC AAC ACC ATC           864                                                                        Gln Thr Leu Ala Pro Ala Ile Asn Trp Leu Pr - #o Phe Leu Asn Thr Ile                    275          - #       280          - #       285                       - - TTC TAC CCC GTG GAG ATC AAT GAA TCC GAG CC - #T ATT GTG GTC TAT GAC           912                                                                        Phe Tyr Pro Val Glu Ile Asn Glu Ser Glu Pr - #o Ile Val Val Tyr Asp                290              - #   295              - #   300                           - - AAG GAA TAC CTT GAG CAG ATC TCC ACT CTC AT - #C AAC ACC ACC GAC AGA           960                                                                        Lys Glu Tyr Leu Glu Gln Ile Ser Thr Leu Il - #e Asn Thr Thr Asp Arg            305                 3 - #10                 3 - #15                 3 -       #20                                                                               - - TGC CTG CTC AAC AAC TAC ATG ATC TGG AAC CT - #G GTG CGG AAA ACA         AGC     1008                                                                     Cys Leu Leu Asn Asn Tyr Met Ile Trp Asn Le - #u Val Arg Lys Thr Ser                           325  - #               330  - #               335               - - TCC TTC CTT GAC CAG CGC TTT CAG GAC GCC GA - #T GAG AAG TTC ATG GAA          1056                                                                        Ser Phe Leu Asp Gln Arg Phe Gln Asp Ala As - #p Glu Lys Phe Met Glu                        340      - #           345      - #           350                   - - GTC ATG TAC GGG ACC AAG AAG ACC TGT CTT CC - #T CGC TGG AAG TTT TGC          1104                                                                        Val Met Tyr Gly Thr Lys Lys Thr Cys Leu Pr - #o Arg Trp Lys Phe Cys                    355          - #       360          - #       365                       - - GTG AGT GAC ACA GAA AAC AAC CTG GGC TTT GC - #G TTG GGC CCC ATG TTT          1152                                                                        Val Ser Asp Thr Glu Asn Asn Leu Gly Phe Al - #a Leu Gly Pro Met Phe                370              - #   375              - #   380                           - - GTC AAA GCA ACC TTC GCC GAG GAC AGC AAG AG - #C ATA GCC ACC GAG ATC          1200                                                                        Val Lys Ala Thr Phe Ala Glu Asp Ser Lys Se - #r Ile Ala Thr Glu Ile            385                 3 - #90                 3 - #95                 4 -       #00                                                                               - - ATC CTG GAG ATT AAG AAG GCA TTT GAG GAA AG - #C CTG AGC ACC CTG         AAG     1248                                                                     Ile Leu Glu Ile Lys Lys Ala Phe Glu Glu Se - #r Leu Ser Thr Leu Lys                           405  - #               410  - #               415               - - TGG ATG GAT GAG GAA ACC CGA AAA TCA GCC AA - #G GAA AAG GCC GAT GCC          1296                                                                        Trp Met Asp Glu Glu Thr Arg Lys Ser Ala Ly - #s Glu Lys Ala Asp Ala                        420      - #           425      - #           430                   - - ATC TAC AAC ATG ATA GGA TAC CCC AAC TTC AT - #C ATG GAT CCC AAG GAG          1344                                                                        Ile Tyr Asn Met Ile Gly Tyr Pro Asn Phe Il - #e Met Asp Pro Lys Glu                    435          - #       440          - #       445                       - - CTG GAC AAA GTG TTT AAT GAC TAC ACT GCA GT - #T CCA GAC CTC TAC TTT          1392                                                                        Leu Asp Lys Val Phe Asn Asp Tyr Thr Ala Va - #l Pro Asp Leu Tyr Phe                450              - #   455              - #   460                           - - GAA AAT GCC ATG CGG TTT TTC AAC TTC TCA TG - #G AGG GTC ACT GCC GAT          1440                                                                        Glu Asn Ala Met Arg Phe Phe Asn Phe Ser Tr - #p Arg Val Thr Ala Asp            465                 4 - #70                 4 - #75                 4 -       #80                                                                               - - CAG CTC AGG AAA GCC CCC AAC AGA GAT CAG TG - #G AGC ATG ACC CCG         CCC     1488                                                                     Gln Leu Arg Lys Ala Pro Asn Arg Asp Gln Tr - #p Ser Met Thr Pro Pro                           485  - #               490  - #               495               - - ATG GTG AAC GCC TAC TAC TCG CCC ACC AAG AA - #T GAG ATT GTG TTT CCG          1536                                                                        Met Val Asn Ala Tyr Tyr Ser Pro Thr Lys As - #n Glu Ile Val Phe Pro                        500      - #           505      - #           510                   - - GCC GGG ATC CTG CAG GCA CCA TTC TAC ACA CG - #C TCC TCA CCC AAG GCC          1584                                                                        Ala Gly Ile Leu Gln Ala Pro Phe Tyr Thr Ar - #g Ser Ser Pro Lys Ala                    515          - #       520          - #       525                       - - TTA AAC TTT GGT GGC ATA GGT GTC GTC GTG GG - #C CAT GAG CTG ACT CAT          1632                                                                        Leu Asn Phe Gly Gly Ile Gly Val Val Val Gl - #y His Glu Leu Thr His                530              - #   535              - #   540                           - - GCT TTT GAT GAT CAA GGA CGG GAG TAT GAC AA - #G GAC GGG AAC CTC CGG          1680                                                                        Ala Phe Asp Asp Gln Gly Arg Glu Tyr Asp Ly - #s Asp Gly Asn Leu Arg            545                 5 - #50                 5 - #55                 5 -       #60                                                                               - - CCA TGG TGG AAG AAC TCA TCC GTG GAG GCC TT - #C AAG CGT CAG ACC         GAG     1728                                                                     Pro Trp Trp Lys Asn Ser Ser Val Glu Ala Ph - #e Lys Arg Gln Thr Glu                           565  - #               570  - #               575               - - TGC ATG GTA GAG CAG TAC AGC AAC TAC AGC GT - #G AAC GGG GAG CCG GTG          1776                                                                        Cys Met Val Glu Gln Tyr Ser Asn Tyr Ser Va - #l Asn Gly Glu Pro Val                        580      - #           585      - #           590                   - - AAC GGG CGG CAC ACC CTG GGG GAG AAC ATC GC - #C GAC AAC GGG GGT CTC          1824                                                                        Asn Gly Arg His Thr Leu Gly Glu Asn Ile Al - #a Asp Asn Gly Gly Leu                    595          - #       600          - #       605                       - - AAG GCG GCC TAT CGG GCT TAC CAG AAC TGG GT - #G AAG AAG AAC GGG GCT          1872                                                                        Lys Ala Ala Tyr Arg Ala Tyr Gln Asn Trp Va - #l Lys Lys Asn Gly Ala                610              - #   615              - #   620                           - - GAG CAC TCG CTC CCC ACC CTG GGC CTC ACC AA - #T AAC CAG CTC TTC TTC          1920                                                                        Glu His Ser Leu Pro Thr Leu Gly Leu Thr As - #n Asn Gln Leu Phe Phe            625                 6 - #30                 6 - #35                 6 -       #40                                                                               - - CTG GGC TTT GCA CAG GTC TGG TGC TCC GTC CG - #C ACA CCT GAG AGC         TCC     1968                                                                     Leu Gly Phe Ala Gln Val Trp Cys Ser Val Ar - #g Thr Pro Glu Ser Ser                           645  - #               650  - #               655               - - CAC GAA GGC CTC ATC ACC GAT CCC CAC AGC CC - #C TCT CGC TTC CGG GTC          2016                                                                        His Glu Gly Leu Ile Thr Asp Pro His Ser Pr - #o Ser Arg Phe Arg Val                        660      - #           665      - #           670                   - - ATC GGC TCC CTC TCC AAT TCC AAG GAG TTC TC - #A GAA CAC TTC CGC TGC          2064                                                                        Ile Gly Ser Leu Ser Asn Ser Lys Glu Phe Se - #r Glu His Phe Arg Cys                    675          - #       680          - #       685                       - - CCA CCT GGC TCA CCC ATG AAC CCG CCT CAC AA - #G TGC GAA GTC TGG              2109                                                                        Pro Pro Gly Ser Pro Met Asn Pro Pro His Ly - #s Cys Glu Val Trp                    690              - #   695              - #   700                           - - TAAGGACGAA GCGGAGAGAG CCAAGACGGA GGAGGGGAAG GGGCTGAGGA CG -              #AGACCCCC   2169                                                                  - - ATCCAGCCTC CAGGGCATTG CTCAGCCCGC TTGGCCACCC GGGGCCCTGC TT -             #CCTCACAC   2229                                                                  - - TGGCGGGTTT TCAGCCGGAA CCGAGCCCAT GGTGTTGGCT CTCAACGTGA CC -             #CGCAGTCT   2289                                                                  - - GATCCCCTGT GAAGAGCCGG ACATCCCAGG CACACGTGTG CGCCACCTTC AG -             #CAGGCATT   2349                                                                  - - CGGGTGCTGG GCTGGTGGCT CATCAGGCCT GGGCCCCACA CTGACAAGCG CC -             #AGATACGC   2409                                                                  - - CACAAATACC ACTGTGTCAA ATGCTTTCAA GATATATTTT TGGGGAAACT AT -             #TTTTTAAA   2469                                                                  - - CACTGTGGAA TACACTGGAA ATCTTCAGGG AAAAACACAT TTAAACACTT TT -             #TTTTTTAA   2529                                                                  - - GCCC                 - #                  - #                  - #                2533                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO: 25:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 703 amino - #acids                                                 (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: protein                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #25:                           - - Arg Leu Val Val Leu Val Val Leu Leu Ala Al - #a Gly Leu Val Ala Cys         1               5 - #                 10 - #                 15               - - Leu Ala Ala Leu Gly Ile Gln Tyr Gln Thr Ar - #g Ser Pro Ser Val Cys                    20     - #             25     - #             30                   - - Leu Ser Glu Ala Cys Val Ser Val Thr Ser Se - #r Ile Leu Ser Ser Met                35         - #         40         - #         45                       - - Asp Pro Thr Val Asp Pro Cys His Asp Phe Ph - #e Ser Tyr Ala Cys Gly            50             - #     55             - #     60                           - - Gly Trp Ile Lys Ala Asn Pro Val Pro Asp Gl - #y His Ser Arg Trp Gly        65                 - # 70                 - # 75                 - # 80        - - Thr Phe Ser Asn Leu Trp Glu His Asn Gln Al - #a Ile Ile Lys His Leu                        85 - #                 90 - #                 95               - - Leu Glu Asn Ser Thr Ala Ser Val Ser Glu Al - #a Glu Arg Lys Ala Gln                   100      - #           105      - #           110                   - - Val Tyr Tyr Arg Ala Cys Met Asn Glu Thr Ar - #g Ile Glu Glu Leu Arg               115          - #       120          - #       125                       - - Ala Lys Pro Leu Met Glu Leu Ile Glu Arg Le - #u Gly Gly Trp Asn Ile           130              - #   135              - #   140                           - - Thr Gly Pro Trp Ala Lys Asp Asn Phe Gln As - #p Thr Leu Gln Val Val       145                 1 - #50                 1 - #55                 1 -       #60                                                                               - - Thr Ala His Tyr Arg Thr Ser Pro Phe Phe Se - #r Val Tyr Val Ser         Ala                                                                                              165  - #               170  - #               175              - - Asp Ser Lys Asn Ser Asn Ser Asn Val Ile Gl - #n Val Asp Gln Ser Gly                   180      - #           185      - #           190                   - - Leu Gly Leu Pro Ser Arg Asp Tyr Tyr Leu As - #n Lys Thr Glu Asn Glu               195          - #       200          - #       205                       - - Lys Val Leu Thr Gly Tyr Leu Asn Tyr Met Va - #l Gln Leu Gly Lys Leu           210              - #   215              - #   220                           - - Leu Gly Gly Gly Asp Glu Glu Ala Ile Arg Pr - #o Gln Met Gln Gln Ile       225                 2 - #30                 2 - #35                 2 -       #40                                                                               - - Leu Asp Phe Glu Thr Ala Leu Ala Asn Ile Th - #r Ile Pro Gln Glu         Lys                                                                                              245  - #               250  - #               255              - - Arg Arg Asp Glu Glu Leu Ile Tyr His Lys Va - #l Thr Ala Ala Glu Leu                   260      - #           265      - #           270                   - - Gln Thr Leu Ala Pro Ala Ile Asn Trp Leu Pr - #o Phe Leu Asn Thr Ile               275          - #       280          - #       285                       - - Phe Tyr Pro Val Glu Ile Asn Glu Ser Glu Pr - #o Ile Val Val Tyr Asp           290              - #   295              - #   300                           - - Lys Glu Tyr Leu Glu Gln Ile Ser Thr Leu Il - #e Asn Thr Thr Asp Arg       305                 3 - #10                 3 - #15                 3 -       #20                                                                               - - Cys Leu Leu Asn Asn Tyr Met Ile Trp Asn Le - #u Val Arg Lys Thr         Ser                                                                                              325  - #               330  - #               335              - - Ser Phe Leu Asp Gln Arg Phe Gln Asp Ala As - #p Glu Lys Phe Met Glu                   340      - #           345      - #           350                   - - Val Met Tyr Gly Thr Lys Lys Thr Cys Leu Pr - #o Arg Trp Lys Phe Cys               355          - #       360          - #       365                       - - Val Ser Asp Thr Glu Asn Asn Leu Gly Phe Al - #a Leu Gly Pro Met Phe           370              - #   375              - #   380                           - - Val Lys Ala Thr Phe Ala Glu Asp Ser Lys Se - #r Ile Ala Thr Glu Ile       385                 3 - #90                 3 - #95                 4 -       #00                                                                               - - Ile Leu Glu Ile Lys Lys Ala Phe Glu Glu Se - #r Leu Ser Thr Leu         Lys                                                                                              405  - #               410  - #               415              - - Trp Met Asp Glu Glu Thr Arg Lys Ser Ala Ly - #s Glu Lys Ala Asp Ala                   420      - #           425      - #           430                   - - Ile Tyr Asn Met Ile Gly Tyr Pro Asn Phe Il - #e Met Asp Pro Lys Glu               435          - #       440          - #       445                       - - Leu Asp Lys Val Phe Asn Asp Tyr Thr Ala Va - #l Pro Asp Leu Tyr Phe           450              - #   455              - #   460                           - - Glu Asn Ala Met Arg Phe Phe Asn Phe Ser Tr - #p Arg Val Thr Ala Asp       465                 4 - #70                 4 - #75                 4 -       #80                                                                               - - Gln Leu Arg Lys Ala Pro Asn Arg Asp Gln Tr - #p Ser Met Thr Pro         Pro                                                                                              485  - #               490  - #               495              - - Met Val Asn Ala Tyr Tyr Ser Pro Thr Lys As - #n Glu Ile Val Phe Pro                   500      - #           505      - #           510                   - - Ala Gly Ile Leu Gln Ala Pro Phe Tyr Thr Ar - #g Ser Ser Pro Lys Ala               515          - #       520          - #       525                       - - Leu Asn Phe Gly Gly Ile Gly Val Val Val Gl - #y His Glu Leu Thr His           530              - #   535              - #   540                           - - Ala Phe Asp Asp Gln Gly Arg Glu Tyr Asp Ly - #s Asp Gly Asn Leu Arg       545                 5 - #50                 5 - #55                 5 -       #60                                                                               - - Pro Trp Trp Lys Asn Ser Ser Val Glu Ala Ph - #e Lys Arg Gln Thr         Glu                                                                                              565  - #               570  - #               575              - - Cys Met Val Glu Gln Tyr Ser Asn Tyr Ser Va - #l Asn Gly Glu Pro Val                   580      - #           585      - #           590                   - - Asn Gly Arg His Thr Leu Gly Glu Asn Ile Al - #a Asp Asn Gly Gly Leu               595          - #       600          - #       605                       - - Lys Ala Ala Tyr Arg Ala Tyr Gln Asn Trp Va - #l Lys Lys Asn Gly Ala           610              - #   615              - #   620                           - - Glu His Ser Leu Pro Thr Leu Gly Leu Thr As - #n Asn Gln Leu Phe Phe       625                 6 - #30                 6 - #35                 6 -       #40                                                                               - - Leu Gly Phe Ala Gln Val Trp Cys Ser Val Ar - #g Thr Pro Glu Ser         Ser                                                                                              645  - #               650  - #               655              - - His Glu Gly Leu Ile Thr Asp Pro His Ser Pr - #o Ser Arg Phe Arg Val                   660      - #           665      - #           670                   - - Ile Gly Ser Leu Ser Asn Ser Lys Glu Phe Se - #r Glu His Phe Arg Cys               675          - #       680          - #       685                       - - Pro Pro Gly Ser Pro Met Asn Pro Pro His Ly - #s Cys Glu Val Trp               690              - #   695              - #   700                           - -  - - (2) INFORMATION FOR SEQ ID NO: 26:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 24 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #26:                           - - GGTGCTTGAT GATGGCTTGG TTGT          - #                  - #                     24                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO: 27:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 24 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #27:                           - - AGATGGAGCT GGTCACCGAG ATGC          - #                  - #                     24                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO: 28:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 324 base - #pairs                                                  (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: cDNA for mRNA                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #28:                           - - GGGAGCGCGG CGCGGGGCCG GAGCGGAGCG CGCGAGCGAT GATGTCTACC TA -              #CAAGCGGC     60                                                                  - - CCACGCTGGA CGAGGAGGAC CTGGTGGACT CGCTGTCCGA GAGCGACGTG TA -             #CCCCAACC    120                                                                  - - ACCTGCAGGT GAACTTCCGA GGCCCCCGGA ACGGCCAGAG ATGCTGGGCC GC -             #CAGGACCC    180                                                                  - - CGGTGGAGAA GCGGCTGGTG GTGCTGGTGG CGCTCCTGGC GGCGGCATTG GT -             #GGCCTGTT    240                                                                  - - TGGCAGTACT GGGCATCCAA TACCAGACAA GAACGCCCTC GGTGTGCCTA AG -             #TGAGGCCT    300                                                                  - - GCATCTCGGT GACCAGCTCC ATCT          - #                  - #                    324                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO: 29:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 2314 base - #pairs                                                 (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: cDNA for mRNA                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #29:                           - - GGGAGCGCGG CGCGGGGCCG GAGCGGAGCG CGCGAGCG ATG ATG TCT - #ACC TAC              53                                                                                           - #                  - #      Met Met Ser Thr Tyr                              - #                  - #        1          - #    5           - - AAG CGG CCC ACG CTG GAC GAG GAG GAC CTG GT - #G GAC TCG CTG TCC GAG           101                                                                        Lys Arg Pro Thr Leu Asp Glu Glu Asp Leu Va - #l Asp Ser Leu Ser Glu                             10 - #                 15 - #                 20               - - AGC GAC GTG TAC CCC AAC CAC CTG CAG GTG AA - #C TTC CGA GGC CCC CGG           149                                                                        Ser Asp Val Tyr Pro Asn His Leu Gln Val As - #n Phe Arg Gly Pro Arg                         25     - #             30     - #             35                   - - AAC GGC CAG AGA TGC TGG GCC GCC AGG ACC CC - #G GTG GAG AAG CGG CTG           197                                                                        Asn Gly Gln Arg Cys Trp Ala Ala Arg Thr Pr - #o Val Glu Lys Arg Leu                     40         - #         45         - #         50                       - - GTG GTG CTG GTG GCG CTC CTG GCG GCG GCA TT - #G GTG GCC TGT TTG GCA           245                                                                        Val Val Leu Val Ala Leu Leu Ala Ala Ala Le - #u Val Ala Cys Leu Ala                 55             - #     60             - #     65                           - - GTA CTG GGC ATC CAA TAC CAG ACA AGA ACG CC - #C TCG GTG TGC CTA AGT           293                                                                        Val Leu Gly Ile Gln Tyr Gln Thr Arg Thr Pr - #o Ser Val Cys Leu Ser             70                 - # 75                 - # 80                 - # 85        - - GAG GCC TGC ATC TCG GTG ACC AGC TCC ATC TT - #G AGT TCC ATG GAC CCC           341                                                                        Glu Ala Cys Ile Ser Val Thr Ser Ser Ile Le - #u Ser Ser Met Asp Pro                             90 - #                 95 - #                100               - - ACG GTG GAC CCC TGC CAG GAC TTC TTC ACC TA - #T GCC TGT GGC GGC TGG           389                                                                        Thr Val Asp Pro Cys Gln Asp Phe Phe Thr Ty - #r Ala Cys Gly Gly Trp                        105      - #           110      - #           115                   - - ATC AAA GCC AAC CCC GTG CCG GAT GGC CAC TC - #G CGC TGG GGG ACC TTC           437                                                                        Ile Lys Ala Asn Pro Val Pro Asp Gly His Se - #r Arg Trp Gly Thr Phe                    120          - #       125          - #       130                       - - AGC AAC CTC TGG GAA CAC AAC CAA GCC ATC AT - #C AAG CAC CTC CTT GAA           485                                                                        Ser Asn Leu Trp Glu His Asn Gln Ala Ile Il - #e Lys His Leu Leu Glu                135              - #   140              - #   145                           - - AAC TCC ACG GCC AGC GTG AGC GAG GCA GAG AG - #G AAG GAC CAG GAG TAC           533                                                                        Asn Ser Thr Ala Ser Val Ser Glu Ala Glu Ar - #g Lys Asp Gln Glu Tyr            150                 1 - #55                 1 - #60                 1 -       #65                                                                               - - TAC CGA GCC TGC ATG AAC GAA ACC AGG ATT GA - #G GAG CTC AAG GCC         AAA      581                                                                     Tyr Arg Ala Cys Met Asn Glu Thr Arg Ile Gl - #u Glu Leu Lys Ala Lys                           170  - #               175  - #               180               - - CCC CTG ATG GAG CTC ATT GAG AAG CTC GGC GG - #C TGG AAC ATC ACG GGG           629                                                                        Pro Leu Met Glu Leu Ile Glu Lys Leu Gly Gl - #y Trp Asn Ile Thr Gly                        185      - #           190      - #           195                   - - CCC TGG GAC AAG GAC AAC TTC CAG GAC ACC CT - #G CAG GTG GTC ACA TCC           677                                                                        Pro Trp Asp Lys Asp Asn Phe Gln Asp Thr Le - #u Gln Val Val Thr Ser                    200          - #       205          - #       210                       - - CAC TAC CAC ACC TCC CCC TTC TTC TCC GTC TA - #C GTC AGT GCC GAC TCC           725                                                                        His Tyr His Thr Ser Pro Phe Phe Ser Val Ty - #r Val Ser Ala Asp Ser                215              - #   220              - #   225                           - - AAG AAT TCC AAC AGC AAC GTG ATC CAA GTG GA - #C CAG TCT GGC CTG GGC           773                                                                        Lys Asn Ser Asn Ser Asn Val Ile Gln Val As - #p Gln Ser Gly Leu Gly            230                 2 - #35                 2 - #40                 2 -       #45                                                                               - - TTA CCC TCA AGA GAT TAT TAC CTG AAC AAA AC - #C GAG AAT GAG AAG         GTG      821                                                                     Leu Pro Ser Arg Asp Tyr Tyr Leu Asn Lys Th - #r Glu Asn Glu Lys Val                           250  - #               255  - #               260               - - CTG ACG GGA TAC CTG AAC TAC ATG GTC CAG CT - #G GGG AAG CTG CTG GGA           869                                                                        Leu Thr Gly Tyr Leu Asn Tyr Met Val Gln Le - #u Gly Lys Leu Leu Gly                        265      - #           270      - #           275                   - - GGA GGG GCC GAG GAC ACC ATC CGG CCC CAG AT - #G CAG CAG ATC CTG GAC           917                                                                        Gly Gly Ala Glu Asp Thr Ile Arg Pro Gln Me - #t Gln Gln Ile Leu Asp                    280          - #       285          - #       290                       - - TTT GAG ACG GCG CTG GCC AAC ATC ACC ATC CC - #C CAG GAG AAG CGC CGG           965                                                                        Phe Glu Thr Ala Leu Ala Asn Ile Thr Ile Pr - #o Gln Glu Lys Arg Arg                295              - #   300              - #   305                           - - GAC GAG GAA CTC ATC TAC CAC AAA GTG ACG GC - #G GCT GAG TTG CAG ACC          1013                                                                        Asp Glu Glu Leu Ile Tyr His Lys Val Thr Al - #a Ala Glu Leu Gln Thr            310                 3 - #15                 3 - #20                 3 -       #25                                                                               - - TTG GCG CCC GCC ATC AAC TGG CTG CCC TTC CT - #C AAC ACC ATC TTC         TAC     1061                                                                     Leu Ala Pro Ala Ile Asn Trp Leu Pro Phe Le - #u Asn Thr Ile Phe Tyr                           330  - #               335  - #               340               - - CCC GTG GAG ATC AAT GAA TCA GAG CCT ATT GT - #C ATC TAC GAC AAA GAA          1109                                                                        Pro Val Glu Ile Asn Glu Ser Glu Pro Ile Va - #l Ile Tyr Asp Lys Glu                        345      - #           350      - #           355                   - - TAC CTG AGC AAG GTC TCC ACC CTC ATC AAC AG - #C ACA GAC AAA TGC CTG          1157                                                                        Tyr Leu Ser Lys Val Ser Thr Leu Ile Asn Se - #r Thr Asp Lys Lys Leu                    360          - #       365          - #       370                       - - CTG AAC AAC TAC ATG ATC TGG AAC CTG GTA CG - #G AAG ACG AGC TCC TTC          1205                                                                        Leu Asn Asn Tyr Met Ile Trp Asn Leu Val Ar - #g Lys Thr Ser Ser Phe                375              - #   380              - #   385                           - - CTC GAT CAG CGC TTC CAG GAC GCC GAC GAG AA - #G TTC ATG GAA GTC ATG          1253                                                                        Leu Asp Gln Arg Phe Gln Asp Ala Asp Glu Ly - #s Phe Met Glu Val Met            390                 3 - #95                 4 - #00                 4 -       #05                                                                               - - TAT GGG ACC AAG AAG ACG TGT CTT CCC CGC TG - #G AAG TTT TGT GTG         AGT     1301                                                                     Tyr Gly Thr Lys Lys Thr Cys Leu Pro Arg Tr - #p Lys Phe Cys Val Ser                           410  - #               415  - #               420               - - GAT ACA GAG AAC ACC TTG GGC TTC GCC CTG GG - #C CCC ATG TTC GTC AAA          1349                                                                        Asp Thr Glu Asn Thr Leu Gly Phe Ala Leu Gl - #y Pro Met Phe Val Lys                        425      - #           430      - #           435                   - - GCG ACC TTC GCT GAG GAC AGC AAG AAC ATA GC - #C AGC GAG ATC ATC CTG          1397                                                                        Ala Thr Phe Ala Glu Asp Ser Lys Asn Ile Al - #a Ser Glu Ile Ile Leu                    440          - #       445          - #       450                       - - GAG ATC AAG AAG GCG TTT GAA GAG AGC CTG AG - #C ACC CTG AAG TGG ATG          1445                                                                        Glu Ile Lys Lys Ala Phe Glu Glu Ser Leu Se - #r Thr Leu Lys Trp Met                455              - #   460              - #   465                           - - GAT GAA GAT ACT CGG AAA TCG GCC AAG GAA AA - #G GCG GAC GCG ATC TAC          1493                                                                        Asp Glu Asp Thr Arg Lys Ser Ala Lys Glu Ly - #s Ala Asp Ala Ile Tyr            470                 4 - #75                 4 - #80                 4 -       #85                                                                               - - AAC ATG ATA GGC TAC CCC AAC TTT ATC ATG GA - #C CCC AAG GAG CTG         GAC     1541                                                                     Asn Met Ile Gly Tyr Pro Asn Phe Ile Met As - #p Pro Lys Glu Leu Asp                           490  - #               495  - #               500               - - AAA GTG TTC AAT GAC TAC ACC GCT GTG CCA GA - #C CTC TAC TTC GAG AAC          1589                                                                        Lys Val Phe Asn Asp Tyr Thr Ala Val Pro As - #p Leu Tyr Phe Glu Asn                        505      - #           510      - #           515                   - - GCC ATG CGG TTT TTC AAC TTC TCC TGG AGG GT - #C ACT GCC GAC CAG CTC          1637                                                                        Ala Met Arg Phe Phe Asn Phe Ser Trp Arg Va - #l Thr Ala Asp Gln Leu                    520          - #       525          - #       530                       - - CGG AAA GCG CCC AAC AGA GAT CAG TGG AGC AT - #G ACC CCG CCC ATG GTG          1685                                                                        Arg Lys Ala Pro Asn Arg Asp Gln Trp Ser Me - #t Thr Pro Pro Met Val                535              - #   540              - #   545                           - - AAC GCC TAC TAC TCG CCC ACC AAG AAC GAG AT - #C GTG TTT CCG GCC GGA          1733                                                                        Asn Ala Tyr Tyr Ser Pro Thr Lys Asn Glu Il - #e Val Phe Pro Ala Gly            550                 5 - #55                 5 - #60                 5 -       #65                                                                               - - ATC CTG CAG GCG CCA TTC TAC ACC CGC TCT TC - #A CCC AAT GCC TTA         AAC     1781                                                                     Ile Leu Gln Ala Pro Phe Tyr Thr Arg Ser Se - #r Pro Asn Ala Leu Asn                           570  - #               575  - #               580               - - TTC GGC GGC ATC GGC GTC GTC GTG GGC CAC GA - #G CTG ACT CAT GCT TTT          1829                                                                        Phe Gly Gly Ile Gly Val Val Val Gly His Gl - #u Leu Thr His Ala Phe                        585      - #           590      - #           595                   - - GAT GAT CAA GGC CGA GAG TAC GAC AAG GAT GG - #G AAC CTC CGG CCC TGG          1877                                                                        Asp Asp Gln Gly Arg Glu Tyr Asp Lys Asp Gl - #y Asn Leu Arg Pro Trp                    600          - #       605          - #       610                       - - TGG AAG AAC TCG TCC GTG GAG GCG TTC AAG CA - #G CAG ACC GCG TGC ATG          1925                                                                        Trp Lys Asn Ser Ser Val Glu Ala Phe Lys Gl - #n Gln Thr Ala Cys Met                615              - #   620              - #   625                           - - GTG GAG CAG TAC GGC AAC TAT AGC GTG AAC GG - #G GAG CCG GTG AAC GGC          1973                                                                        Val Glu Gln Tyr Gly Asn Tyr Ser Val Asn Gl - #y Glu Pro Val Asn Gly            630                 6 - #35                 6 - #40                 6 -       #45                                                                               - - CGG CAC ACC CTC GGC GAA AAC ATC GCC GAC AA - #C GGG GGC CTC AAG         GCG     2021                                                                     Arg His Thr Leu Gly Glu Asn Ile Ala Asp As - #n Gly Gly Leu Lys Ala                           650  - #               655  - #               660               - - GCC TAT CGG GCC TAC CAG AAC TGG GTC AAG AA - #G AAT GGG GCT GAG CAG          2069                                                                        Ala Tyr Arg Ala Tyr Gln Asn Trp Val Lys Ly - #s Asn Gly Ala Glu Gln                        665      - #           670      - #           675                   - - ACA CTG CCC ACC CTG GGT CTC ACC AAC AAC CA - #G CTC TTC TTC CTG AGT          2117                                                                        Thr Leu Pro Thr Leu Gly Leu Thr Asn Asn Gl - #n Leu Phe Phe Leu Ser                    680          - #       685          - #       690                       - - TTT GCA CAG GTC TGG TGT TCC GTC CGC ACC CC - #C GAG AGT TCG CAC GAA          2165                                                                        Phe Ala Gln Val Trp Cys Ser Val Arg Thr Pr - #o Glu Ser Ser His Glu                695              - #   700              - #   705                           - - GGT CTC ATC ACC GAT CCC CAC AGC CCC TCC CG - #C TTC CGG GTC ATC GGC          2213                                                                        Gly Leu Ile Thr Asp Pro His Ser Pro Ser Ar - #g Phe Arg Val Ile Gly            710                 7 - #15                 7 - #20                 7 -       #25                                                                               - - TCC ATC TCC AAC TCC AAG GAG TTC TCG GAA CA - #C TTC CAC TGC CCG         CCC     2261                                                                     Ser Ile Ser Asn Ser Lys Glu Phe Ser Glu Hi - #s Phe His Cys Pro Pro                           730  - #               735  - #               740               - - GGC TCA CCC ATG AAC CCG CAT CAC AAG TGT GA - #A GTC TGG T GAAGGGCCAG         2311                                                                        Gly Ser Pro Met Asn Pro His His Lys Cys Gl - #u Val Trp                                    745      - #           750                                          - - GCA                  - #                  - #                  - #                2314                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO: 30:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 754 amino - #acids                                                 (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: protein                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #30:                           - - Met Met Ser Thr Tyr Lys Arg Pro Thr Leu As - #p Glu Glu Asp Leu Val         1               5 - #                 10 - #                 15               - - Asp Ser Leu Ser Glu Ser Asp Val Tyr Pro As - #n His Leu Gln Val Asn                    20     - #             25     - #             30                   - - Phe Arg Gly Pro Arg Asn Gly Gln Arg Cys Tr - #p Ala Ala Arg Thr Pro                35         - #         40         - #         45                       - - Val Glu Lys Arg Leu Val Val Leu Val Ala Le - #u Leu Ala Ala Ala Leu            50             - #     55             - #     60                           - - Val Ala Cys Leu Ala Val Leu Gly Ile Gln Ty - #r Gln Thr Arg Thr Pro        65                 - # 70                 - # 75                 - # 80        - - Ser Val Cys Leu Ser Glu Ala Cys Ile Ser Va - #l Thr Ser Ser Ile Leu                        85 - #                 90 - #                 95               - - Ser Ser Met Asp Pro Thr Val Asp Pro Cys Gl - #n Asp Phe Phe Thr Tyr                   100      - #           105      - #           110                   - - Ala Cys Gly Gly Trp Ile Lys Ala Asn Pro Va - #l Pro Asp Gly His Ser               115          - #       120          - #       125                       - - Arg Trp Gly Thr Phe Ser Asn Leu Trp Glu Hi - #s Asn Gln Ala Ile Ile           130              - #   135              - #   140                           - - Lys His Leu Leu Glu Asn Ser Thr Ala Ser Va - #l Ser Glu Ala Glu Arg       145                 1 - #50                 1 - #55                 1 -       #60                                                                               - - Lys Asp Gln Glu Tyr Tyr Arg Ala Cys Met As - #n Glu Thr Arg Ile         Glu                                                                                              165  - #               170  - #               175              - - Glu Leu Lys Ala Lys Pro Leu Met Glu Leu Il - #e Glu Lys Leu Gly Gly                   180      - #           185      - #           190                   - - Trp Asn Ile Thr Gly Pro Trp Asp Lys Asp As - #n Phe Gln Asp Thr Leu               195          - #       200          - #       205                       - - Gln Val Val Thr Ser His Tyr His Thr Ser Pr - #o Phe Phe Ser Val Tyr           210              - #   215              - #   220                           - - Val Ser Ala Asp Ser Lys Asn Ser Asn Ser As - #n Val Ile Gln Val Asp       225                 2 - #30                 2 - #35                 2 -       #40                                                                               - - Gln Ser Gly Leu Gly Leu Pro Ser Arg Asp Ty - #r Tyr Leu Asn Lys         Thr                                                                                              245  - #               250  - #               255              - - Glu Asn Glu Lys Val Leu Thr Gly Tyr Leu As - #n Tyr Met Val Gln Leu                   260      - #           265      - #           270                   - - Gly Lys Leu Leu Gly Gly Gly Ala Glu Asp Th - #r Ile Arg Pro Gln Met               275          - #       280          - #       285                       - - Gln Gln Ile Leu Asp Phe Glu Thr Ala Leu Al - #a Asn Ile Thr Ile Pro           290              - #   295              - #   300                           - - Gln Glu Lys Arg Arg Asp Glu Glu Leu Ile Ty - #r His Lys Val Thr Ala       305                 3 - #10                 3 - #15                 3 -       #20                                                                               - - Ala Glu Leu Gln Thr Leu Ala Pro Ala Ile As - #n Trp Leu Pro Phe         Leu                                                                                              325  - #               330  - #               335              - - Asn Thr Ile Phe Tyr Pro Val Glu Ile Asn Gl - #u Ser Glu Pro Ile Val                   340      - #           345      - #           350                   - - Ile Tyr Asp Lys Glu Tyr Leu Ser Lys Val Se - #r Thr Leu Ile Asn Ser               355          - #       360          - #       365                       - - Thr Asp Lys Cys Leu Leu Asn Asn Tyr Met Il - #e Trp Asn Leu Val Arg           370              - #   375              - #   380                           - - Lys Thr Ser Ser Phe Leu Asp Gln Arg Phe Gl - #n Asp Ala Asp Glu Lys       385                 3 - #90                 3 - #95                 4 -       #00                                                                               - - Phe Met Glu Val Met Tyr Gly Thr Lys Lys Th - #r Cys Leu Pro Arg         Trp                                                                                              405  - #               410  - #               415              - - Lys Phe Cys Val Ser Asp Thr Glu Asn Thr Le - #u Gly Phe Ala Leu Gly                   420      - #           425      - #           430                   - - Pro Met Phe Val Lys Ala Thr Phe Ala Glu As - #p Ser Lys Asn Ile Ala               435          - #       440          - #       445                       - - Ser Glu Ile Ile Leu Glu Ile Lys Lys Ala Ph - #e Glu Glu Ser Leu Ser           450              - #   455              - #   460                           - - Thr Leu Lys Trp Met Asp Glu Asp Thr Arg Ly - #s Ser Ala Lys Glu Lys       465                 4 - #70                 4 - #75                 4 -       #80                                                                               - - Ala Asp Ala Ile Tyr Asn Met Ile Gly Tyr Pr - #o Asn Phe Ile Met         Asp                                                                                              485  - #               490  - #               495              - - Pro Lys Glu Leu Asp Lys Val Phe Asn Asp Ty - #r Thr Ala Val Pro Asp                   500      - #           505      - #           510                   - - Leu Tyr Phe Glu Asn Ala Met Arg Phe Phe As - #n Phe Ser Trp Arg Val               515          - #       520          - #       525                       - - Thr Ala Asp Gln Leu Arg Lys Ala Pro Asn Ar - #g Asp Gln Trp Ser Met           530              - #   535              - #   540                           - - Thr Pro Pro Met Val Asn Ala Tyr Tyr Ser Pr - #o Thr Lys Asn Glu Ile       545                 5 - #50                 5 - #55                 5 -       #60                                                                               - - Val Phe Pro Ala Gly Ile Leu Gln Ala Pro Ph - #e Tyr Thr Arg Ser         Ser                                                                                              565  - #               570  - #               575              - - Pro Asn Ala Leu Asn Phe Gly Gly Ile Gly Va - #l Val Val Gly His Glu                   580      - #           585      - #           590                   - - Leu Thr His Ala Phe Asp Asp Gln Gly Arg Gl - #u Tyr Asp Lys Asp Gly               595          - #       600          - #       605                       - - Asn Leu Arg Pro Trp Trp Lys Asn Ser Ser Va - #l Glu Ala Phe Lys Gln           610              - #   615              - #   620                           - - Gln Thr Ala Cys Met Val Glu Gln Tyr Gly As - #n Tyr Ser Val Asn Gly       625                 6 - #30                 6 - #35                 6 -       #40                                                                               - - Glu Pro Val Asn Gly Arg His Thr Leu Gly Gl - #u Asn Ile Ala Asp         Asn                                                                                              645  - #               650  - #               655              - - Gly Gly Leu Lys Ala Ala Tyr Arg Ala Tyr Gl - #n Asn Trp Val Lys Lys                   660      - #           665      - #           670                   - - Asn Gly Ala Glu Gln Thr Leu Pro Thr Leu Gl - #y Leu Thr Asn Asn Gln               675          - #       680          - #       685                       - - Leu Phe Phe Leu Ser Phe Ala Gln Val Trp Cy - #s Ser Val Arg Thr Pro           690              - #   695              - #   700                           - - Glu Ser Ser His Glu Gly Leu Ile Thr Asp Pr - #o His Ser Pro Ser Arg       705                 7 - #10                 7 - #15                 7 -       #20                                                                               - - Phe Arg Val Ile Gly Ser Ile Ser Asn Ser Ly - #s Glu Phe Ser Glu         His                                                                                              725  - #               730  - #               735              - - Phe His Cys Pro Pro Gly Ser Pro Met Asn Pr - #o His His Lys Cys Glu                   740      - #           745      - #           750                   - - Val Trp                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO: 31:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 53 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #31:                           - - GAGAGAGAGA GAGAGAGAGA ACTAGTCTCG AGCCAAGCAG GCCACCAGTC CT - #G                 53                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO: 32:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 25 base - #pairs                                                   (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: genomic DNA                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #32:                           - - CCTGCCGCCA GAAGTACCAC CAACA          - #                  - #                    25                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO: 33:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 222 base - #pairs                                                  (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: cDNA for mRNA                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #33:                           - - CGCCCCCCCG GTGTCCGCCC TGCTGTCGGC GCTGGGG ATG TCG ACG - #TAC AAG CGG           55                                                                                           - #                  - #     Met Ser Thr Tyr Lys Arg                           - #                  - #       1           - #    5           - - GCC ACG CTG GAC GAG GAG GAC CTG GTG GAC TC - #G CTC TCC GAG GGC GAC           103                                                                        Ala Thr Leu Asp Glu Glu Asp Leu Val Asp Se - #r Leu Ser Glu Gly Asp                         10     - #             15     - #             20                   - - GCA TAC CCC AAC GGC CTG CAG GTG AAC TTC CA - #C AGC CCC CGG AGT GGC           151                                                                        Ala Tyr Pro Asn Gly Leu Gln Val Asn Phe Hi - #s Ser Pro Arg Ser Gly                     25         - #         30         - #         35                       - - CAG AGG TGC TGG GCT GCA CGG ACC CAG GTG GA - #G AAG CGG CTG GTG GTG           199                                                                        Gln Arg Cys Trp Ala Ala Arg Thr Gln Val Gl - #u Lys Arg Leu Val Val                 40             - #     45             - #     50                           - - TTG GTG GTA CTT CTG GCG GCA GG      - #                  - #                    222                                                                      Leu Val Val Leu Leu Ala Ala                                                     55                 - # 60                                                      - -  - - (2) INFORMATION FOR SEQ ID NO: 34:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 61 amino - #acids                                                  (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: protein                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #34:                           - - Met Ser Thr Tyr Lys Arg Ala Thr Leu Asp Gl - #u Glu Asp Leu Val Asp         1               5 - #                 10 - #                 15               - - Ser Leu Ser Glu Gly Asp Ala Tyr Pro Asn Gl - #y Leu Gln Val Asn Phe                    20     - #             25     - #             30                   - - His Ser Pro Arg Ser Gly Gln Arg Cys Trp Al - #a Ala Arg Thr Gln Val                35         - #         40         - #         45                       - - Glu Lys Arg Leu Val Val Leu Val Val Leu Le - #u Ala Ala                        50             - #     55             - #     60                           - -  - - (2) INFORMATION FOR SEQ ID NO: 35:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 2720 base - #pairs                                                 (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: cDNA for mRNA                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #35:                           - - CGCCCCCCCG GTGTCCGCCC TGCTGTCGGC GCTGGGG ATG TCG ACG - #TAC AAG CGG           55                                                                                           - #                  - #     Met Ser Thr Tyr Lys Arg                           - #                  - #       1           - #    5           - - GCC ACG CTG GAC GAG GAG GAC CTG GTG GAC TC - #G CTC TCC GAG GGC GAC           103                                                                        Ala Thr Leu Asp Glu Glu Asp Leu Val Asp Se - #r Leu Ser Glu Gly Asp                         10     - #             15     - #             20                   - - GCA TAC CCC AAC GGC CTG CAG GTG AAC TTC CA - #C AGC CCC CGG AGT GGC           151                                                                        Ala Tyr Pro Asn Gly Leu Gln Val Asn Phe Hi - #s Ser Pro Arg Ser Gly                     25         - #         30         - #         35                       - - CAG AGG TGC TGG GCT GCA CGG ACC CAG GTG GA - #G AAG CGG CTG GTG GTG           199                                                                        Gln Arg Cys Trp Ala Ala Arg Thr Gln Val Gl - #u Lys Arg Leu Val Val                 40             - #     45             - #     50                           - - TTG GTG GTA CTT CTG GCG GCA GGA CTG GTG GC - #C TGC TTG GCA GCA CTG           247                                                                        Leu Val Val Leu Leu Ala Ala Gly Leu Val Al - #a Cys Leu Ala Ala Leu             55                 - # 60                 - # 65                 - # 70        - - GGC ATC CAG TAC CAG ACA AGA TCC CCC TCT GT - #G TGC CTG AGC GAA GCT           295                                                                        Gly Ile Gln Tyr Gln Thr Arg Ser Pro Ser Va - #l Cys Leu Ser Glu Ala                             75 - #                 80 - #                 85               - - TGT GTC TCA GTG ACC AGC TCC ATC TTG AGC TC - #C ATG GAC CCC ACA GTG           343                                                                        Cys Val Ser Val Thr Ser Ser Ile Leu Ser Se - #r Met Asp Pro Thr Val                         90     - #             95     - #            100                   - - GAC CCC TGC CAT GAC TTC TTC AGC TAC GCC TG - #T GGG GGC TGG ATC AAG           391                                                                        Asp Pro Cys His Asp Phe Phe Ser Tyr Ala Cy - #s Gly Gly Trp Ile Lys                    105          - #       110          - #       115                       - - GCC AAC CCA GTC CCT GAT GGC CAC TCA CGC TG - #G GGG ACC TTC AGC AAC           439                                                                        Ala Asn Pro Val Pro Asp Gly His Ser Arg Tr - #p Gly Thr Phe Ser Asn                120              - #   125              - #   130                           - - CTC TGG GAA CAC AAC CAA GCA ATC ATC AAG CA - #C CTC CTC GAA AAC TCC           487                                                                        Leu Trp Glu His Asn Gln Ala Ile Ile Lys Hi - #s Leu Leu Glu Asn Ser            135                 1 - #40                 1 - #45                 1 -       #50                                                                               - - ACG GCC AGC GTG AGC GAG GCA GAG AGA AAG GC - #G CAA GTA TAC TAC         CGT      535                                                                     Thr Ala Ser Val Ser Glu Ala Glu Arg Lys Al - #a Gln Val Tyr Tyr Arg                           155  - #               160  - #               165               - - GCG TGC ATG AAC GAG ACC AGG ATC GAG GAG CT - #C AGG GCC AAA CCT CTA           583                                                                        Ala Cys Met Asn Glu Thr Arg Ile Glu Glu Le - #u Arg Ala Lys Pro Leu                        170      - #           175      - #           180                   - - ATG GAG TTG ATT GAG AGG CTC GGG GGC TGG AA - #C ATC ACA GGT CCC TGG           631                                                                        Met Glu Leu Ile Glu Arg Leu Gly Gly Trp As - #n Ile Thr Gly Pro Trp                    185          - #       190          - #       195                       - - GCC AAG GAC AAC TTC CAG GAC ACC CTG CAG GT - #G GTC ACC GCC CAC TAC           679                                                                        Ala Lys Asp Asn Phe Gln Asp Thr Leu Gln Va - #l Val Thr Ala His Tyr                200              - #   205              - #   210                           - - CGC ACC TCA CCC TTC TTC TCT GTC TAT GTC AG - #T GCC GAT TCC AAG AAC           727                                                                        Arg Thr Ser Pro Phe Phe Ser Val Tyr Val Se - #r Ala Asp Ser Lys Asn            215                 2 - #20                 2 - #25                 2 -       #30                                                                               - - TCC AAC AGC AAC GTG ATC CAG GTG GAC CAG TC - #T GGC CTG GGC TTG         CCC      775                                                                     Ser Asn Ser Asn Val Ile Gln Val Asp Gln Se - #r Gly Leu Gly Leu Pro                           235  - #               240  - #               245               - - TCG AGA GAC TAT TAC CTG AAC AAA ACT GAA AA - #C GAG AAG GTG CTG ACC           823                                                                        Ser Arg Asp Tyr Tyr Leu Asn Lys Thr Glu As - #n Glu Lys Val Leu Thr                        250      - #           255      - #           260                   - - GGA TAT CTG AAC TAC ATG GTC CAG CTG GGG AA - #G CTG CTG GGC GGC GGG           871                                                                        Gly Tyr Leu Asn Tyr Met Val Gln Leu Gly Ly - #s Leu Leu Gly Gly Gly                    265          - #       270          - #       275                       - - GAC GAG GAG GCC ATC CGG CCC CAG ATG CAG CA - #G ATC TTG GAC TTT GAG           919                                                                        Asp Glu Glu Ala Ile Arg Pro Gln Met Gln Gl - #n Ile Leu Asp Phe Glu                280              - #   285              - #   290                           - - ACG GCA CTG GCC AAC ATC ACC ATC CCA CAG GA - #G AAG CGC CGT GAT GAG           967                                                                        Thr Ala Leu Ala Asn Ile Thr Ile Pro Gln Gl - #u Lys Arg Arg Asp Glu            295                 3 - #00                 3 - #05                 3 -       #10                                                                               - - GAG CTC ATC TAC CAC AAA GTG ACG GCA GCC GA - #G CTG CAG ACC TTG         GCA     1015                                                                     Glu Leu Ile Tyr His Lys Val Thr Ala Ala Gl - #u Leu Gln Thr Leu Ala                           315  - #               320  - #               325               - - CCC GCC ATC AAC TGG TTG CCT TTT CTC AAC AC - #C ATC TTC TAC CCC GTG          1063                                                                        Pro Ala Ile Asn Trp Leu Pro Phe Leu Asn Th - #r Ile Phe Tyr Pro Val                        330      - #           335      - #           340                   - - GAG ATC AAT GAA TCC GAG CCT ATT GTG GTC TA - #T GAC AAG GAA TAC CTT          1111                                                                        Glu Ile Asn Glu Ser Glu Pro Ile Val Val Ty - #r Asp Lys Glu Tyr Leu                    345          - #       350          - #       355                       - - GAG CAG ATC TCC ACT CTC ATC AAC ACC ACC GA - #C AGA TGC CTG CTC AAC          1159                                                                        Glu Gln Ile Ser Thr Leu Ile Asn Thr Thr As - #p Arg Cys Leu Leu Asn                360              - #   365              - #   370                           - - AAC TAC ATG ATC TGG AAC CTG GTG CGG AAA AC - #A AGC TCC TTC CTT GAC          1207                                                                        Asn Tyr Met Ile Trp Asn Leu Val Arg Lys Th - #r Ser Ser Phe Leu Asp            375                 3 - #80                 3 - #85                 3 -       #90                                                                               - - CAG CGC TTT CAG GAC GCC GAT GAG AAG TTC AT - #G GAA GTC ATG TAC         GGG     1255                                                                     Gln Arg Phe Gln Asp Ala Asp Glu Lys Phe Me - #t Glu Val Met Tyr Gly                           395  - #               400  - #               405               - - ACC AAG AAG ACC TGT CTT CCT CGC TGG AAG TT - #T TGC GTG AGT GAC ACA          1303                                                                        Thr Lys Lys Thr Cys Leu Pro Arg Trp Lys Ph - #e Cys Val Ser Asp Thr                        410      - #           415      - #           420                   - - GAA AAC AAC CTG GGC TTT GCG TTG GGC CCC AT - #G TTT GTC AAA GCA ACC          1351                                                                        Glu Asn Asn Leu Gly Phe Ala Leu Gly Pro Me - #t Phe Val Lys Ala Thr                    425          - #       430          - #       435                       - - TTC GCC GAG GAC AGC AAG AGC ATA GCC ACC GA - #G ATC ATC CTG GAG ATT          1399                                                                        Phe Ala Glu Asp Ser Lys Ser Ile Ala Thr Gl - #u Ile Ile Leu Glu Ile                440              - #   445              - #   450                           - - AAG AAG GCA TTT GAG GAA AGC CTG AGC ACC CT - #G AAG TGG ATG GAT GAG          1447                                                                        Lys Lys Ala Phe Glu Glu Ser Leu Ser Thr Le - #u Lys Trp Met Asp Glu            455                 4 - #60                 4 - #65                 4 -       #70                                                                               - - GAA ACC CGA AAA TCA GCC AAG GAA AAG GCC GA - #T GCC ATC TAC AAC         ATG     1495                                                                     Glu Thr Arg Lys Ser Ala Lys Glu Lys Ala As - #p Ala Ile Tyr Asn Met                           475  - #               480  - #               485               - - ATA GGA TAC CCC AAC TTC ATC ATG GAT CCC AA - #G GAG CTG GAC AAA GTG          1543                                                                        Ile Gly Tyr Pro Asn Phe Ile Met Asp Pro Ly - #s Glu Leu Asp Lys Val                        490      - #           495      - #           500                   - - TTT AAT GAC TAC ACT GCA GTT CCA GAC CTC TA - #C TTT GAA AAT GCC ATG          1591                                                                        Phe Asn Asp Tyr Thr Ala Val Pro Asp Leu Ty - #r Phe Glu Asn Ala Met                    505          - #       510          - #       515                       - - CGG TTT TTC AAC TTC TCA TGG AGG GTC ACT GC - #C GAT CAG CTC AGG AAA          1639                                                                        Arg Phe Phe Asn Phe Ser Trp Arg Val Thr Al - #a Asp Gln Leu Arg Lys                520              - #   525              - #   530                           - - GCC CCC AAC AGA GAT CAG TGG AGC ATG ACC CC - #G CCC ATG GTG AAC GCC          1687                                                                        Ala Pro Asn Arg Asp Gln Trp Ser Met Thr Pr - #o Pro Met Val Asn Ala            535                 5 - #40                 5 - #45                 5 -       #50                                                                               - - TAC TAC TCG CCC ACC AAG AAT GAG ATT GTG TT - #T CCG GCC GGG ATC         CTG     1735                                                                     Tyr Tyr Ser Pro Thr Lys Asn Glu Ile Val Ph - #e Pro Ala Gly Ile Leu                           555  - #               560  - #               565               - - CAG GCA CCA TTC TAC ACA CGC TCC TCA CCC AA - #G GCC TTA AAC TTT GGT          1783                                                                        Gln Ala Pro Phe Tyr Thr Arg Ser Ser Pro Ly - #s Ala Leu Asn Phe Gly                        570      - #           575      - #           580                   - - GGC ATA GGT GTC GTC GTG GGC CAT GAG CTG AC - #T CAT GCT TTT GAT GAT          1831                                                                        Gly Ile Gly Val Val Val Gly His Glu Leu Th - #r His Ala Phe Asp Asp                    585          - #       590          - #       595                       - - CAA GGA CGG GAG TAT GAC AAG GAC GGG AAC CT - #C CGG CCA TGG TGG AAG          1879                                                                        Gln Gly Arg Glu Tyr Asp Lys Asp Gly Asn Le - #u Arg Pro Trp Trp Lys                600              - #   605              - #   610                           - - AAC TCA TCC GTG GAG GCC TTC AAG CGT CAG AC - #C GAG TGC ATG GTA GAG          1927                                                                        Asn Ser Ser Val Glu Ala Phe Lys Arg Gln Th - #r Glu Cys Met Val Glu            615                 6 - #20                 6 - #25                 6 -       #30                                                                               - - CAG TAC AGC AAC TAC AGC GTG AAC GGG GAG CC - #G GTG AAC GGG CGG         CAC     1975                                                                     Gln Tyr Ser Asn Tyr Ser Val Asn Gly Glu Pr - #o Val Asn Gly Arg His                           635  - #               640  - #               645               - - ACC CTG GGG GAG AAC ATC GCC GAC AAC GGG GG - #T CTC AAG GCG GCC TAT          2023                                                                        Thr Leu Gly Glu Asn Ile Ala Asp Asn Gly Gl - #y Leu Lys Ala Ala Tyr                        650      - #           655      - #           660                   - - CGG GCT TAC CAG AAC TGG GTG AAG AAG AAC GG - #G GCT GAG CAC TCG CTC          2071                                                                        Arg Ala Tyr Gln Asn Trp Val Lys Lys Asn Gl - #y Ala Glu His Ser Leu                    665          - #       670          - #       675                       - - CCC ACC CTG GGC CTC ACC AAT AAC CAG CTC TT - #C TTC CTG GGC TTT GCA          2119                                                                        Pro Thr Leu Gly Leu Thr Asn Asn Gln Leu Ph - #e Phe Leu Gly Phe Ala                680              - #   685              - #   690                           - - CAG GTC TGG TGC TCC GTC CGC ACA CCT GAG AG - #C TCC CAC GAA GGC CTC          2167                                                                        Gln Val Trp Cys Ser Val Arg Thr Pro Glu Se - #r Ser His Glu Gly Leu            695                 7 - #00                 7 - #05                 7 -       #10                                                                               - - ATC ACC GAT CCC CAC AGC CCC TCT CGC TTC CG - #G GTC ATC GGC TCC         CTC     2215                                                                     Ile Thr Asp Pro His Ser Pro Ser Arg Phe Ar - #g Val Ile Gly Ser Leu                           715  - #               720  - #               725               - - TCC AAT TCC AAG GAG TTC TCA GAA CAC TTC CG - #C TGC CCA CCT GGC TCA          2263                                                                        Ser Asn Ser Lys Glu Phe Ser Glu His Phe Ar - #g Cys Pro Pro Gly Ser                        730      - #           735      - #           740                   - - CCC ATG AAC CCG CCT CAC AAG TGC GAA GTC TG - #G T AAGGACGAAG                 230 - #7                                                                    Pro Met Asn Pro Pro His Lys Cys Glu Val Tr - #p                                        745          - #       750                                              - - CGGAGAGAGC CAAGACGGAG GAGGGGAAGG GGCTGAGGAC GAGACCCCCA TC -              #CAGCCTCC   2367                                                                  - - AGGGCATTGC TCAGCCCGCT TGGCCACCCG GGGCCCTGCT TCCTCACACT GG -             #CGGGTTTT   2427                                                                  - - CAGCCGGAAC CGAGCCCATG GTGTTGGCTC TCAACGTGAC CCGCAGTCTG AT -             #CCCCTGTG   2487                                                                  - - AAGAGCCGGA CATCCCAGGC ACACGTGTGC GCCACCTTCA GCAGGCATTC GG -             #GTGCTGGG   2547                                                                  - - CTGGTGGCTC ATCAGGCCTG GGCCCCACAC TGACAAGCGC CAGATACGCC AC -             #AAATACCA   2607                                                                  - - CTGTGTCAAA TGCTTTCAAG ATATATTTTT GGGGAAACTA TTTTTTAAAC AC -             #TGTGGAAT   2667                                                                  - - ACACTGGAAA TCTTCAGGGA AAAACACATT TAAACACTTT TTTTTTTAAG CC - #C               2720                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO: 36:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 753 amino - #acids                                                 (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                  - -     (ii) MOLECULE TYPE: protein                                            - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #36:                           - - Met Ser Thr Tyr Lys Arg Ala Thr Leu Asp Gl - #u Glu Asp Leu Val Asp         1               5 - #                 10 - #                 15               - - Ser Leu Ser Glu Gly Asp Ala Tyr Pro Asn Gl - #y Leu Gln Val Asn Phe                    20     - #             25     - #             30                   - - His Ser Pro Arg Ser Gly Gln Arg Cys Trp Al - #a Ala Arg Thr Gln Val                35         - #         40         - #         45                       - - Glu Lys Arg Leu Val Val Leu Val Val Leu Le - #u Ala Ala Gly Leu Val            50             - #     55             - #     60                           - - Ala Cys Leu Ala Ala Leu Gly Ile Gln Tyr Gl - #n Thr Arg Ser Pro Ser        65                 - # 70                 - # 75                 - # 80        - - Val Cys Leu Ser Glu Ala Cys Val Ser Val Th - #r Ser Ser Ile Leu Ser                        85 - #                 90 - #                 95               - - Ser Met Asp Pro Thr Val Asp Pro Cys His As - #p Phe Phe Ser Tyr Ala                   100      - #           105      - #           110                   - - Cys Gly Gly Trp Ile Lys Ala Asn Pro Val Pr - #o Asp Gly His Ser Arg               115          - #       120          - #       125                       - - Trp Gly Thr Phe Ser Asn Leu Trp Glu His As - #n Gln Ala Ile Ile Lys           130              - #   135              - #   140                           - - His Leu Leu Glu Asn Ser Thr Ala Ser Val Se - #r Glu Ala Glu Arg Lys       145                 1 - #50                 1 - #55                 1 -       #60                                                                               - - Ala Gln Val Tyr Tyr Arg Ala Cys Met Asn Gl - #u Thr Arg Ile Glu         Glu                                                                                              165  - #               170  - #               175              - - Leu Arg Ala Lys Pro Leu Met Glu Leu Ile Gl - #u Arg Leu Gly Gly Trp                   180      - #           185      - #           190                   - - Asn Ile Thr Gly Pro Trp Ala Lys Asp Asn Ph - #e Gln Asp Thr Leu Gln               195          - #       200          - #       205                       - - Val Val Thr Ala His Tyr Arg Thr Ser Pro Ph - #e Phe Ser Val Tyr Val           210              - #   215              - #   220                           - - Ser Ala Asp Ser Lys Asn Ser Asn Ser Asn Va - #l Ile Gln Val Asp Gln       225                 2 - #30                 2 - #35                 2 -       #40                                                                               - - Ser Gly Leu Gly Leu Pro Ser Arg Asp Tyr Ty - #r Leu Asn Lys Thr         Glu                                                                                              245  - #               250  - #               255              - - Asn Glu Lys Val Leu Thr Gly Tyr Leu Asn Ty - #r Met Val Gln Leu Gly                   260      - #           265      - #           270                   - - Lys Leu Leu Gly Gly Gly Asp Glu Glu Ala Il - #e Arg Pro Gln Met Gln               275          - #       280          - #       285                       - - Gln Ile Leu Asp Phe Glu Thr Ala Leu Ala As - #n Ile Thr Ile Pro Gln           290              - #   295              - #   300                           - - Glu Lys Arg Arg Asp Glu Glu Leu Ile Tyr Hi - #s Lys Val Thr Ala Ala       305                 3 - #10                 3 - #15                 3 -       #20                                                                               - - Glu Leu Gln Thr Leu Ala Pro Ala Ile Asn Tr - #p Leu Pro Phe Leu         Asn                                                                                              325  - #               330  - #               335              - - Thr Ile Phe Tyr Pro Val Glu Ile Asn Glu Se - #r Glu Pro Ile Val Val                   340      - #           345      - #           350                   - - Tyr Asp Lys Glu Tyr Leu Glu Gln Ile Ser Th - #r Leu Ile Asn Thr Thr               355          - #       360          - #       365                       - - Asp Arg Cys Leu Leu Asn Asn Tyr Met Ile Tr - #p Asn Leu Val Arg Lys           370              - #   375              - #   380                           - - Thr Ser Ser Phe Leu Asp Gln Arg Phe Gln As - #p Ala Asp Glu Lys Phe       385                 3 - #90                 3 - #95                 4 -       #00                                                                               - - Met Glu Val Met Tyr Gly Thr Lys Lys Thr Cy - #s Leu Pro Arg Trp         Lys                                                                                              405  - #               410  - #               415              - - Phe Cys Val Ser Asp Thr Glu Asn Asn Leu Gl - #y Phe Ala Leu Gly Pro                   420      - #           425      - #           430                   - - Met Phe Val Lys Ala Thr Phe Ala Glu Asp Se - #r Lys Ser Ile Ala Thr               435          - #       440          - #       445                       - - Glu Ile Ile Leu Glu Ile Lys Lys Ala Phe Gl - #u Glu Ser Leu Ser Thr           450              - #   455              - #   460                           - - Leu Lys Trp Met Asp Glu Glu Thr Arg Lys Se - #r Ala Lys Glu Lys Ala       465                 4 - #70                 4 - #75             480             - - Asp Ala Ile Tyr Asn Met Ile Gly Tyr Pro As - #n Phe Ile Met Asp Pro                       485  - #               490  - #               495               - - Lys Glu Leu Asp Lys Val Phe Asn Asp Tyr Th - #r Ala Val Pro Asp Leu                   500      - #           505      - #           510                   - - Tyr Phe Glu Asn Ala Met Arg Phe Phe Asn Ph - #e Ser Trp Arg Val Thr               515          - #       520          - #       525                       - - Ala Asp Gln Leu Arg Lys Ala Pro Asn Arg As - #p Gln Trp Ser Met Thr           530              - #   535              - #   540                           - - Pro Pro Met Val Asn Ala Tyr Tyr Ser Pro Th - #r Lys Asn Glu Ile Val       545                 5 - #50                 5 - #55                 5 -       #60                                                                               - - Phe Pro Ala Gly Ile Leu Gln Ala Pro Phe Ty - #r Thr Arg Ser Ser         Pro                                                                                              565  - #               570  - #               575              - - Lys Ala Leu Asn Phe Gly Gly Ile Gly Val Va - #l Val Gly His Glu Leu                   580      - #           585      - #           590                   - - Thr His Ala Phe Asp Asp Gln Gly Arg Glu Ty - #r Asp Lys Asp Gly Asn               595          - #       600          - #       605                       - - Leu Arg Pro Trp Trp Lys Asn Ser Ser Val Gl - #u Ala Phe Lys Arg Gln           610              - #   615              - #   620                           - - Thr Glu Cys Met Val Glu Gln Tyr Ser Asn Ty - #r Ser Val Asn Gly Glu       625                 6 - #30                 6 - #35                 6 -       #40                                                                               - - Pro Val Asn Gly Arg His Thr Leu Gly Glu As - #n Ile Ala Asp Asn         Gly                                                                                              645  - #               650  - #               655              - - Gly Leu Lys Ala Ala Tyr Arg Ala Tyr Gln As - #n Trp Val Lys Lys Asn                   660      - #           665      - #           670                   - - Gly Ala Glu His Ser Leu Pro Thr Leu Gly Le - #u Thr Asn Asn Gln Leu               675          - #       680          - #       685                       - - Phe Phe Leu Gly Phe Ala Gln Val Trp Cys Se - #r Val Arg Thr Pro Glu           690              - #   695              - #   700                           - - Ser Ser His Glu Gly Leu Ile Thr Asp Pro Hi - #s Ser Pro Ser Arg Phe       705                 7 - #10                 7 - #15                 7 -       #20                                                                               - - Arg Val Ile Gly Ser Leu Ser Asn Ser Lys Gl - #u Phe Ser Glu His         Phe                                                                                              725  - #               730  - #               735              - - Arg Cys Pro Pro Gly Ser Pro Met Asn Pro Pr - #o His Lys Cys Glu Val                   740      - #           745      - #           750                   - - Trp                                                                      __________________________________________________________________________ 

What is claimed is:
 1. An isolated endothelin converting enzyme having an amino acid sequence described in SEQ ID NO:
 36. 2. An isolated DNA encoding an endothelin converting enzyme defined in claim 1 and having a nucleotide sequence shown in SEQ ID NO:
 35. 3. A method of expressing a DNA having a sequence encoding endothelin converting enzyme with an amino acid sequence shown in SEQ ID NO: 36, which method comprises(a) isolating a DNA sequence which hybridizes under stringent conditions with a probe consisting of a DNA fragment of SEQ ID NO: 36, or a sequence-complementary DNA fragment; (b) ligating said DNA sequence to an expression vector and introducing said vector into a host cell; and (c) measuring the endothelin converting enzyme activity of the transformed cell.
 4. A method of identifying an inhibitor of endothelin converting enzyme, which method comprises exposing a substrate to the endothelin converting enzyme defined in claim 1 in the presence of a possible inhibitor, and inspecting the substrate for cleavage; wherein an inhibitor of endothelin converting enzyme is positively identified when the substrate is cleaved. 